Publications by year
In Press
Patinha D, Pijacka W, Paton JFR, Koeners MPM (In Press). Cooperative oxygen sensing by the kidney and carotid body in blood pressure control. Frontiers in Physiology
Vara D, Tarafdar A, Celikag M, Souto Patinha D, Gulacsy CE, Hounslea E, Warren Z, Ferreira B, Koeners MP, Caggiano L, et al (In Press). NADPH oxidase 1 is a novel pharmacological target for the development of an antiplatelet drug without bleeding side effects. The FASEB Journal
Meor Azlan NF, Koeners MP, Zhang J (In Press). Regulatory control of the Na–Cl co-transporter NCC and its therapeutic potential for hypertension.
Abstract:
Regulatory control of the Na–Cl co-transporter NCC and its therapeutic potential for hypertension
Abstract.
2022
Koeners M (2022). Exploring the benefits of compassion – in education and in life. Excellence in Education.
Web link.
Kight C, Comley S, Koeners M (2022). Playful University: supporting the link between joy and learning. Joint Information Systems Committee (JISC).
Web link.
2021
Koeners M (2021). Becoming a playful academic: a personal story. British Educational research Association (BERA).
Web link.
Koeners M, Gilbert I (2021). Playful creativity. British Educational research Association (BERA).
Web link.
Koeners M, Kight C (2021). Playful purpose: using games to connect and inspire. Excellence in Education.
Web link.
Meor Azlan NF, Koeners MP, Zhang J (2021). Regulatory control of the Na–Cl co-transporter NCC and its therapeutic potential for hypertension. Acta Pharmaceutica Sinica B, 11(5), 1117-1128.
Koeners M (2021). The playful academic. British Educational research Association (BERA).
Web link.
2020
Patinha D, Koeners M (2020). Renal blood flow and oxygen metabolism in renovascular hypertension.
Author URL.
Koeners MP, Francis J (2020). The physiology of play: potential relevance for higher education.
International Journal of Play,
9(1), 143-159.
Abstract:
The physiology of play: potential relevance for higher education
This paper explores the physiology of play and its potential for advancing higher education through promoting joy and counteracting performativity, which we argue is a proponent of mental ill-health in the sector. Although play is increasingly recognised as a fundamental part of the human experience and a successful teaching practice, it is only consistently applied within childhood education. We identify 3 key areas of play physiology relevant for higher education: physical and mental resilience; social intelligence; cognitive flexibility and intellect. We conclude that the incorporation of play within higher education by developing ‘Playful Universities’ could counteract the fear of failing, avoidance of risk and other negative aspects of performativity and goal-oriented behaviour. Playful learning, therefore, challenges the continued relevance of focusing on a dehumanising and oppressive neoliberal model of performativity-based learning and sheds light on the potential of a joyous, authentic transition to the co-creation of knowledge within higher education.
Abstract.
2019
Koeners MPM, Adamovich Y, Ladeuix B, Sobel J, Manella G, Neufeld-Cohen A, Assadi MH, Golik M, Kuperman Y, Tarasiuk A, et al (2019). Oxygen and Carbon Dioxide Rhythms Are Circadian Clock Controlled and Differentially Directed by Behavioral Signals. Cell Metabolism, 29
2018
Ow CPC, Ngo JP, Ullah MM, Barsha G, Meex RC, Watt MJ, Hilliard LM, Koeners MP, Evans RG (2018). Absence of renal hypoxia in the subacute phase of severe renal ischemia-reperfusion injury.
Am J Physiol Renal Physiol,
315(5), F1358-F1369.
Abstract:
Absence of renal hypoxia in the subacute phase of severe renal ischemia-reperfusion injury.
Tissue hypoxia has been proposed as an important event in renal ischemia-reperfusion injury (IRI), particularly during the period of ischemia and in the immediate hours following reperfusion. However, little is known about renal oxygenation during the subacute phase of IRI. We employed four different methods to assess the temporal and spatial changes in tissue oxygenation during the subacute phase (24 h and 5 days after reperfusion) of a severe form of renal IRI in rats. We hypothesized that the kidney is hypoxic 24 h and 5 days after an hour of bilateral renal ischemia, driven by a disturbed balance between renal oxygen delivery (Do2) and oxygen consumption (V̇o2). Renal Do2 was not significantly reduced in the subacute phase of IRI. In contrast, renal V̇o2 was 55% less 24 h after reperfusion and 49% less 5 days after reperfusion than after sham ischemia. Inner medullary tissue Po2, measured by radiotelemetry, was 25 ± 12% (mean ± SE) greater 24 h after ischemia than after sham ischemia. By 5 days after reperfusion, tissue Po2 was similar to that in rats subjected to sham ischemia. Tissue Po2 measured by Clark electrode was consistently greater 24 h, but not 5 days, after ischemia than after sham ischemia. Cellular hypoxia, assessed by pimonidazole adduct immunohistochemistry, was largely absent at both time points, and tissue levels of hypoxia-inducible factors were downregulated following renal ischemia. Thus, in this model of severe IRI, tissue hypoxia does not appear to be an obligatory event during the subacute phase, likely because of the markedly reduced oxygen consumption.
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Author URL.
Emans TW, Patinha D, Joles JA, Koeners MP, Janssen BJ, Krediet CTP (2018). Angiotensin II-induced hypertension in rats is only transiently accompanied by lower renal oxygenation.
Sci Rep,
8(1).
Abstract:
Angiotensin II-induced hypertension in rats is only transiently accompanied by lower renal oxygenation.
Activation of the renin-angiotensin system may initiate chronic kidney disease. We hypothesised that renal hypoxia is a consequence of hemodynamic changes induced by angiotensin II and occurs prior to development of severe renal damage. Male Sprague-Dawley rats were infused continuously with angiotensin II (350 ng/kg/min) for 8 days. Mean arterial pressure (n = 5), cortical (n = 6) and medullary (n = 7) oxygenation (pO2) were continuously recorded by telemetry and renal tissue injury was scored. Angiotensin II increased arterial pressure gradually to 150 ± 18 mmHg. This was associated with transient reduction of oxygen levels in renal cortex (by 18 ± 2%) and medulla (by 17 ± 6%) at 10 ± 2 and 6 ± 1 hours, respectively after starting infusion. Thereafter oxygen levels normalised to pre-infusion levels and were maintained during the remainder of the infusion period. In rats receiving angiotensin II, adding losartan to drinking water (300 mg/L) only induced transient increase in renal oxygenation, despite normalisation of arterial pressure. In rats, renal hypoxia is only a transient phenomenon during initiation of angiotensin II-induced hypertension.
Abstract.
Author URL.
Palm F, Koeners MP (2018). Editorial: Hypoxia in Kidney Disease.
FRONTIERS IN PHYSIOLOGY,
9 Author URL.
2016
Emans TW, Janssen BJ, Pinkham MI, Ow CPC, Evans RG, Joles JA, Malpas SC, Krediet CTP, Koeners MP (2016). Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow.
J Physiol,
594(21), 6287-6300.
Abstract:
Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow.
KEY POINTS: Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary. We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats. This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation. Exogenous angiotensin-II reduced renal cortical tissue PO2 more than equi-pressor doses of phenylephrine, probably because it reduced renal oxygen delivery more than did phenylephrine. Activation of the endogenous renin-angiotensin system in transgenic Cyp1a1Ren2 rats reduced cortical tissue PO2; in this model renal hypoxia precedes the development of structural pathology and can be reversed acutely by an angiotensin-II receptor type 1 antagonist. Angiotensin-II promotes renal hypoxia, which may in turn contribute to its pathological effects during development of chronic kidney disease. ABSTRACT: We hypothesised that both exogenous and endogenous angiotensin-II (AngII) can decrease the partial pressure of oxygen (PO2) in the renal cortex of unrestrained rats, which might in turn contribute to the progression of chronic kidney disease. Rats were instrumented with telemeters equipped with a carbon paste electrode for continuous measurement of renal cortical tissue PO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PO2 was dose-dependently reduced by intravenous AngII. Reductions in PO2 were significantly greater than those induced by equi-pressor doses of phenylephrine. In anaesthetised rats, renal oxygen consumption was not affected, and filtration fraction was increased only in the AngII infused animals. Oxygen delivery decreased by 50% after infusion of AngII and renal blood flow (RBF) fell by 3.3 ml min-1. Equi-pressor infusion of phenylephrine did not significantly reduce RBF or renal oxygen delivery. Activation of the endogenous renin-angiotensin system in Cyp1a1Ren2 transgenic rats reduced cortical tissue PO2. This could be reversed within minutes by pharmacological angiotensin-II receptor type 1 (AT1 R) blockade. Thus AngII is an important modulator of renal cortical oxygenation via AT1 receptors. AngII had a greater influence on cortical oxygenation than did phenylephrine. This phenomenon appears to be attributable to the profound impact of AngII on renal oxygen delivery. We conclude that the ability of AngII to promote renal cortical hypoxia may contribute to its influence on initiation and progression of chronic kidney disease.
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Author URL.
Koeners MP, Lewis KE, Ford AP, Paton JF (2016). Hypertension: a problem of organ blood flow supply-demand mismatch.
Future Cardiol,
12(3), 339-349.
Abstract:
Hypertension: a problem of organ blood flow supply-demand mismatch.
This review introduces a new hypothesis that sympathetically mediated hypertensive diseases are caused, in the most part, by the activation of visceral afferent systems that are connected to neural circuits generating sympathetic activity. We consider how organ hypoperfusion and blood flow supply-demand mismatch might lead to both sensory hyper-reflexia and aberrant afferent tonicity. We discuss how this may drive sympatho-excitatory-positive feedback and extend across multiple organs initiating, or at least amplifying, sympathetic hyperactivity. The latter, in turn, compounds the challenge to sufficient organ blood flow through heightened vasoconstriction that both maintains and exacerbates hypertension.
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Koeners MP, Wesseling S, Sánchez M, Braam B, Joles JA (2016). Perinatal Inhibition of NF-KappaB Has Long-Term Antihypertensive and Renoprotective Effects in Fawn-Hooded Hypertensive Rats.
Am J Hypertens,
29(1), 123-131.
Abstract:
Perinatal Inhibition of NF-KappaB Has Long-Term Antihypertensive and Renoprotective Effects in Fawn-Hooded Hypertensive Rats.
BACKGROUND: Inhibition of transcription factor nuclear factor-kappa B (NFκB) is beneficial in various models of hypertension and renal disease. We hypothesized first that NFκB inhibition during renal development ameliorates hereditary hypertensive renal disease and next whether this was mediated via suppression of peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α). METHODS AND RESULTS: Prior to the development of renal injury in fawn-hooded hypertensive (FHH) rats, a model of hypertension, glomerular hyperfiltration, and progressive renal injury, NFkB activity, measured by nuclear protein expression of NFkB subunit p65, was enhanced twofold in 2-day-old male and female FHH kidneys as compared to normotensive Wistar-Kyoto (WKY) rats (P < 0.05). Treating FHH dams with pyrrolidine di thio carbamate (PDTC), an NFκB inhibitor, from 2 weeks before birth to 4 weeks after birth diminished NFkB activity in 2-day-FHH offspring to 2-day-WKY levels (P < 0.01). Perinatal PDTC reduced systolic blood pressure from 20 weeks onwards by on average 25 mm Hg (P < 0.001) and ameliorated proteinuria (P < 0.05) and glomerulosclerosis (P < 0.05). In kidneys of 2-day-, 2-week-, and adult offspring of PDTC-treated FHH dams, PGC-1α was induced on average by 67% (quantitative polymerase chain reaction (qPCR)) suggesting that suppression of this factor by NFkB could be involved in renal damage. Follow-up experiments with perinatal pioglitazone (Pio), a PPARγ agonist, failed to confer persistent antihypertensive or renoprotective effects. CONCLUSIONS: Perinatal inhibition of enhanced active renal NFκB in 2-day FHH had persistent antihypertensive and renoprotective effects. However, this was not the case for PPARγ stimulation. NFkB stimulation is therefore involved in renal damage in the FHH model of proteinuric renal disease by pathways other than via PPARγ.
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Koeners MP, Ow CPC, Russell DM, Evans RG, Malpas SC (2016). Prolonged and Continuous Measurement of Kidney Oxygenation in Conscious Rats.
Methods Mol Biol,
1397, 93-111.
Abstract:
Prolonged and Continuous Measurement of Kidney Oxygenation in Conscious Rats.
A relative deficiency in kidney oxygenation, i.e. renal hypoxia, may contribute to the initiation and progression of acute and chronic kidney disease. A critical barrier to investigate this is the lack of methods allowing measurement of the partial pressure of oxygen in kidney tissue for long periods in vivo. We have developed, validated, and tested a novel telemetric method that can do this. Here we provide details on the calibration, implantation, implementation for data recording, and reuse of this telemetry-based technology for measurement of medullary tissue oxygen tension in conscious, unrestrained rats. This technique provides an important additional tool for investigating the impact of renal hypoxia in biology and pathophysiology.
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Emans TW, Koeners MP, Joles JA, Janssen BJ, Krediet CTP (2016). RENAL OXYGENATION DURING CHRONIC ANGIOTENSIN II INFUSION IN CONCIOUS RATS.
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Gerritsen KGF, Bovenschen N, Nguyen TQ, Sprengers D, Koeners MP, van Koppen AN, Joles JA, Goldschmeding R, Kok RJ (2016). Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis.
J Cell Commun Signal,
10(4), 295-303.
Abstract:
Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis.
CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min). Immunosorbent assay and immunostaining showed that CCN-2 distributed mainly to the liver and was taken up by hepatocytes. Steady state clearance in rats, determined by continuous infusion of CCN-2, was fast (45 mL/kg/min). Renal CCN-2 clearance, determined by arterial and renal vein sampling, accounted for only 12 % of total clearance. Co-infusion of CCN-2 with receptor-associated protein (RAP), an antagonist of LDL-receptor family proteins, showed that RAP prolonged CCN-2 half-life and completely prevented CCN-2 internalization by hepatocytes. This suggests that hepatic uptake of CCN-2 is mediated by a RAP-sensitive mechanism most likely involving LRP1, a member of the LDL-receptor family involved in hepatic clearance of various plasma proteins. Surface plasmon resonance binding studies confirmed that CCN-2 is an LRP1 ligand. Co-infusion of CCN-2 with an excess of the heparan sulphate-binding protamine lowered the large initial distribution volume of CCN-2 by 88 % and reduced interstitial staining of CCN-2, suggesting binding of CCN-2 to heparan sulphate proteoglycans (HSPGs). Protamine did not affect clearance rate, indicating that RAP-sensitive clearance of CCN-2 is HSPG independent. In conclusion, unlike its amino-terminal fragment which is cleared by the kidney, full length CCN-2 is primarily eliminated by the liver via a fast RAP-sensitive, probably LRP1-dependent pathway.
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Adamovich Y, Ladeuix B, Golik M, Koeners MP, Asher G (2016). Rhythmic Oxygen Levels Reset Circadian Clocks through HIF1α. CELL METABOLISM, 25(1), 93-101.
Emans TW, Koeners MP, Joles JA, Janssen BJ, Krediet CTP (2016). SP076RENAL OXYGENATION DURING CHRONIC ANGIOTENSIN II INFUSION IN CONCIOUS RATS. Nephrology Dialysis Transplantation, 31(suppl_1), i111-i111.
Tomiak-Baquero AM, Lewis KE, Roloff E, Kasparov S, Koeners MP, Paton JFR (2016). Using Fiber-Optic Confocal Microscopy for in Vivo Imaging of Brain and Kidney Vasculature and Haemodynamics.
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2015
Gerritsen KGF, Leeuwis JW, Koeners MP, Bakker SJL, van Oeveren W, Aten J, Tarnow L, Rossing P, Wetzels JFM, Joles JA, et al (2015). Elevated Urinary Connective Tissue Growth Factor in Diabetic Nephropathy is Caused by Local Production and Tubular Dysfunction.
J Diabetes Res,
2015Abstract:
Elevated Urinary Connective Tissue Growth Factor in Diabetic Nephropathy is Caused by Local Production and Tubular Dysfunction.
Connective tissue growth factor (CTGF; CCN2) plays a role in the development of diabetic nephropathy (DN). Urinary CTGF (uCTGF) is elevated in DN patients and has been proposed as a biomarker for disease progression, but it is unknown which pathophysiological factors contribute to elevated uCTGF. We studied renal handling of CTGF by infusion of recombinant CTGF in diabetic mice. In addition, uCTGF was measured in type 1 DN patients and compared with glomerular and tubular dysfunction and damage markers. In diabetic mice, uCTGF was increased and fractional excretion (FE) of recombinant CTGF was substantially elevated indicating reduced tubular reabsorption. FE of recombinant CTGF correlated with excretion of endogenous CTGF. CTGF mRNA was mainly localized in glomeruli and medullary tubules. Comparison of FE of endogenous and recombinant CTGF indicated that 60% of uCTGF had a direct renal source, while 40% originated from plasma CTGF. In DN patients, uCTGF was independently associated with markers of proximal and distal tubular dysfunction and damage. In conclusion, uCTGF in DN is elevated as a result of both increased local production and reduced reabsorption due to tubular dysfunction. We submit that uCTGF is a biomarker reflecting both glomerular and tubulointerstitial hallmarks of diabetic kidney disease.
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Koeners M, Lewis K, Paton J (2015). Telemetric Recording of Renal and Carotid Blood Flow Velocity and Arterial Blood Pressure Simultaneously in Rats.
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Emans T, Koeners M, Joles J, Krediet CT, Debets J, Janssen B (2015). Telemetry‐based Recording of Renal Cortex Oxygenation During Endogenous RAS Activation: Preliminary Observations. The FASEB Journal, 29(S1).
2014
Koeners MP, Braam B, Joles JA (2014). Blood pressure follows the kidney. Organogenesis, 4(3), 153-157.
Papazova DA, Friederich-Persson M, Koeners MP, Joles JA, Verhaar MC (2014). DONOR PRETREATMENT WITH MITOTEMPO DECREASES MITOCHONDRIAL UNCOUPLING AFTER EXPERIMENTAL RENAL TRANSPLANTATION.
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Ow CPC, Tassone F, Koeners MP, Malpas SC, Evans RG (2014). KIDNEY OXYGENATION DURING ACUTE SALINE VOLUME LOADING IN UNANESTHETIZED RATS.
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Evans R, Ow C, Abdelkader A, Hilliard L, Malpas S, Koeners M (2014). Kidney oxygenation in the subacute phase of ischemia‐reperfusion injury (890.1). The FASEB Journal, 28(S1).
Papazova DA, van Koppen A, Koeners MP, Bleys RL, Verhaar MC, Joles JA (2014). Maintenance of hypertensive hemodynamics does not depend on ROS in established experimental chronic kidney disease.
PLoS One,
9(2).
Abstract:
Maintenance of hypertensive hemodynamics does not depend on ROS in established experimental chronic kidney disease.
While the presence of oxidative stress in chronic kidney disease (CKD) is well established, its relation to hypertensive renal hemodynamics remains unclear. We hypothesized that once CKD is established blood pressure and renal vascular resistance (RVR) no longer depend on reactive oxygen species. CKD was induced by bilateral ablation of 2/3 of each kidney. Compared to age-matched, sham-operated controls all ablated rats showed proteinuria, decreased glomerular filtration rate (GFR), more renal damage, higher mean arterial pressure (MAP), RVR and excretion of oxidative stress markers and hydrogen peroxide, while excretion of stable nitric oxide (NO) metabolites tended to decrease. We compared MAP, RVR, GFR and fractional excretion of sodium under baseline and during acute Tempol, PEG-catalase or vehicle infusion in rats with established CKD vs. controls. Tempol caused marked reduction in MAP in controls (96±5 vs.79±4 mmHg, P
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Koeners MP, Vink EE, Kuijper A, Gadellaa N, Rosenberger C, Mathia S, Van Den Meiracker AH, Garrelds IM, Blankestijn PJ, Joles JA, et al (2014). Stabilization of hypoxia inducible factor-1α ameliorates acute renal neurogenic hypertension.
Journal of Hypertension,
32(3), 587-597.
Abstract:
Stabilization of hypoxia inducible factor-1α ameliorates acute renal neurogenic hypertension
Obectives: Renal neurogenic hypertension (RNH) contributes to cardiovascular morbidity. Renal hypoxia may cause RNH and vice versa, leading to a vicious circle. Hypoxia adaptation is conferred through hypoxia-inducible factors (HIFs). We hypothesized that acute RNH is accompanied by increased renal vascular resistance (RVR) and that hypertension and increased RVR are countered by increasing HIF-1α by cobalt chloride (CoCl2) preconditioning. Methods: First, we studied mean arterial pressure (MAP) and RVR in innervated or denervated contralateral kidneys in anesthetized rats before and after unilateral intrarenal injection of phenol, a manoeuvre known to elicit acute RNH. Then HIFα was induced by CoCl2 in drinking water (2mM, 10 days) after which we compared intrarenal isotonic saline or phenol injection on MAP and RVR in CoCl2 preconditioned and control rats. HIF-1α was determined by immunohistochemistry. Results: Unilateral intrarenal phenol induced immediate rise in MAP and contralateral RVR, and comparable HIF-1α upregulation in both kidneys, consistent with bi-renal hypoxia. Removing the phenol-injected kidney immediately normalized MAP. Contralateral renal denervation had no effect on the rise in MAP, but abrogated the contralateral increase in RVR, suggesting mediation by increased efferent nerve activity. Strong renal staining for HIF-1α confirmed efficacy of CoCl2 preconditioning, and time-dependent increase in heme oxygenase-1 gene expression stabilization of HIFα. CoCl2 preconditioning prior to phenol reduced both ΔMAP (+10 ± 2 vs. +20±3%, P=0.015) and ΔRVR (+21±11 vs. +90±26%, P=0.003). Conclusion: Acute RNH leads to renal vasoconstriction and increased renal HIF-1α. Increasing HIF-1α by CoCl2 preconditioning ameliorates intrarenal phenol-induced RNH and renal vasoconstriction. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Abstract.
Koeners MP, Vink EE, Kuijper A, Gadellaa N, Rosenberger C, Mathia S, van den Meiracker AH, Garrelds IM, Blankestijn PJ, Joles JA, et al (2014). Stabilization of hypoxia inducible factor-1α ameliorates acute renal neurogenic hypertension.
J Hypertens,
32(3), 587-597.
Abstract:
Stabilization of hypoxia inducible factor-1α ameliorates acute renal neurogenic hypertension.
OBJECTIVES: Renal neurogenic hypertension (RNH) contributes to cardiovascular morbidity. Renal hypoxia may cause RNH and vice versa, leading to a vicious circle. Hypoxia adaptation is conferred through hypoxia-inducible factors (HIFs). We hypothesized that acute RNH is accompanied by increased renal vascular resistance (RVR) and that hypertension and increased RVR are countered by increasing HIF-1α by cobalt chloride (CoCl2) preconditioning. METHODS: First, we studied mean arterial pressure (MAP) and RVR in innervated or denervated contralateral kidneys in anesthetized rats before and after unilateral intrarenal injection of phenol, a manoeuvre known to elicit acute RNH. Then HIFα was induced by CoCl2 in drinking water (2 mM, 10 days) after which we compared intrarenal isotonic saline or phenol injection on MAP and RVR in CoCl2 preconditioned and control rats. HIF-1α was determined by immunohistochemistry. RESULTS: Unilateral intrarenal phenol induced immediate rise in MAP and contralateral RVR, and comparable HIF-1α upregulation in both kidneys, consistent with bi-renal hypoxia. Removing the phenol-injected kidney immediately normalized MAP. Contralateral renal denervation had no effect on the rise in MAP, but abrogated the contralateral increase in RVR, suggesting mediation by increased efferent nerve activity. Strong renal staining for HIF-1α confirmed efficacy of CoCl2 preconditioning, and time-dependent increase in heme oxygenase-1 gene expression stabilization of HIFα. CoCl2 preconditioning prior to phenol reduced both ΔMAP (+10 ± 2 vs. +20 ± 3%, P=0.015) and ΔRVR (+21 ± 11 vs. +90 ± 26%, P=0.003). CONCLUSION: Acute RNH leads to renal vasoconstriction and increased renal HIF-1α. Increasing HIF-1α by CoCl2 preconditioning ameliorates intrarenal phenol-induced RNH and renal vasoconstriction.
Abstract.
Author URL.
Emans TW, Ow CP, Joles JA, Evans RG, Malpas SC, Koeners MP (2014). TELEMETRY-BASED RECORDING OF RENAL CORTICAL OXYGENATION IN RESPONSE TO ANGIOTENSIN-II AND PHENYLEPHRINE IN THE CONSCIOUS RAT.
Author URL.
Koeners M, Emans T, Ow C, Evans R, Malpas S (2014). Telemetry‐based recording of renal cortical oxygenation in conscious rats with chronic kidney disease (890.4). The FASEB Journal, 28(S1).
2013
Koeners MP, Ow CPC, Russell DM, Abdelkader A, Eppel GA, Ludbrook J, Malpas SC, Evans RG (2013). Telemetry-based oxygen sensor for continuous monitoring of kidney oxygenation in conscious rats.
Am J Physiol Renal Physiol,
304(12), F1471-F1480.
Abstract:
Telemetry-based oxygen sensor for continuous monitoring of kidney oxygenation in conscious rats.
The precise roles of hypoxia in the initiation and progression of kidney disease remain unresolved. A major technical limitation has been the absence of methods allowing long-term measurement of kidney tissue oxygen tension (Po₂) in unrestrained animals. We developed a telemetric method for the measurement of kidney tissue Po₂ in unrestrained rats, using carbon paste electrodes (CPEs). After acute implantation in anesthetized rats, tissue Po₂ measured by CPE-telemetry in the inner cortex and medulla was in close agreement with that provided by the "gold standard" Clark electrode. The CPE-telemetry system could detect small changes in renal tissue Po₂ evoked by mild hypoxemia. In unanesthetized rats, CPE-telemetry provided stable measurements of medullary tissue Po₂ over days 5-19 after implantation. It also provided reproducible responses to systemic hypoxia and hyperoxia over this time period. There was little evidence of fibrosis or scarring after 3 wk of electrode implantation. However, because medullary Po₂ measured by CPE-telemetry was greater than that documented from previous studies in anesthetized animals, this method is presently best suited for monitoring relative changes rather than absolute values. Nevertheless, this new technology provides, for the first time, the opportunity to examine the temporal relationships between tissue hypoxia and the progression of renal disease.
Abstract.
Author URL.
Koeners MP, Ow CPC, Evans RG, Russell DM, Joles JA, Malpas S (2013). Telemetry-based oxygen sensor to continuously monitor renal cortical oxygenation in the conscious rat.
Author URL.
2012
Ow CPC, Koeners M, Abdelkader A, Evans RG, Russell DM, Malpas S (2012). 286 TELEMETRY-BASED OXYGEN SENSOR TO CONTINUOUSLY MONITOR KIDNEY OXYGENATION IN CONSCIOUS RATS; a NEW PLATFORM FOR EXPLORING DEVELOPMENT OF RENAL DISEASE. Journal of Hypertension, 30(&NA;).
Gerritsen KG, Abrahams AC, Peters HP, Nguyen TQ, Koeners MP, den Hoedt CH, Dendooven A, van den Dorpel MA, Blankestijn PJ, Wetzels JF, et al (2012). Effect of GFR on plasma N-terminal connective tissue growth factor (CTGF) concentrations.
Am J Kidney Dis,
59(5), 619-627.
Abstract:
Effect of GFR on plasma N-terminal connective tissue growth factor (CTGF) concentrations.
BACKGROUND: Connective tissue growth factor (CTGF) has a key role in the pathogenesis of renal and cardiac fibrosis. Its amino-terminal fragment (N-CTGF), the predominant form of CTGF detected in plasma, has a molecular weight in the middle molecular range (18 kDa). However, it is unknown whether N-CTGF is a uremic retention solute that accumulates in chronic kidney disease (CKD) due to decreased renal clearance and whether it can be removed by hemodiafiltration. STUDY DESIGN: 4 observational studies in patients and 2 pharmacokinetic studies in rodents. SETTING & PARTICIPANTS: 4 single-center studies. First study (cross-sectional): 88 patients with CKD not receiving kidney replacement therapy. Second study (cross-sectional): 23 patients with end-stage kidney disease undergoing low-flux hemodialysis. Third study: 9 kidney transplant recipients before and 6 months after transplant. Fourth study: 11 low-flux hemodialysis patients and 12 hemodiafiltration patients before and after one dialysis session. PREDICTOR: First, second, and third study: (residual) glomerular filtration rate (GFR). Fourth study: dialysis modality. OUTCOMES & MEASUREMENTS: Plasma (N-)CTGF concentrations, measured by enzyme-linked immunosorbent assay. RESULTS: in patients with CKD, we observed an independent association between plasma CTGF level and estimated GFR (β = -0.72; P < 0.001). In patients with end-stage kidney disease, plasma CTGF level correlated independently with residual kidney function (β = -0.55; P = 0.046). Successful kidney transplant resulted in a decrease in plasma CTGF level (P = 0.008) proportional to the increase in estimated GFR. Plasma CTGF was not removed by low-flux hemodialysis, whereas it was decreased by 68% by a single hemodiafiltration session (P < 0.001). Pharmacokinetic studies in nonuremic rodents confirmed that renal clearance is the major elimination route of N-CTGF. LIMITATIONS: Observational studies with limited number of patients. Fourth study: nonrandomized, evaluation of the effect of one session; randomized longitudinal study is warranted. CONCLUSION: Plasma (N-)CTGF is eliminated predominantly by the kidney, accumulates in CKD, and is decreased substantially by a single hemodiafiltration session.
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Sima CA, Koeners MP, Joles JA, Braam B, Magil AB, Cupples WA (2012). Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake.
Diabetologia,
55(8), 2246-2255.
Abstract:
Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake.
AIMS/HYPOTHESIS: in early type 1 diabetes mellitus, renal salt handling is dysregulated, so that the glomerular filtration rate becomes inversely proportional to salt intake. The salt paradox occurs in both humans and rats and, with low salt intake, results in diabetic hyperfiltration. We tested whether increased salt intake could reduce the susceptibility to injury of non-clipped kidneys in diabetic rats with pre-existing Goldblatt hypertension. METHODS: Male Long-Evans rats were made hypertensive and half were then made diabetic. Blood glucose was maintained at ~20-25 mmol/l by insulin implants. One half of each received only the salt in normal chow (1% by weight) and the other half received added salt in drinking water to equal 2.7% by weight of food intake. Weekly 24 h blood pressure records were acquired by telemetry during the 4-month experiment. RESULTS: Systolic blood pressure was not affected by diabetes or increased salt intake, alone or together. Autoregulation was highly efficient in the non-clipped kidney of both intact and diabetic rats. Histological examination showed minor injury in the clipped kidney, which did not differ among groups. The non-clipped kidney showed extensive pressure-dependent glomerular and vascular injury in both intact and diabetic rats. CONCLUSIONS/INTERPRETATION: the relationship between pressure and injury was shifted toward lower blood pressure in diabetic rats, indicating that diabetes increased the susceptibility of the kidney to injury despite preservation of autoregulation. The increased susceptibility was not affected by high salt intake in the diabetic rats, thus disproving the hypothesis.
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Author URL.
Koeners M, Ow P, Abdelkader A, Verhaar MC, Evans RG, Russell DM, Joles JA, Malpas S (2012). Telemetry‐based oxygen sensor to continuously monitor kidney oxygenation in conscious rats. The FASEB Journal, 26(S1), 690.6-690.6.
Koeners M, Ow P, Abdelkader A, Papazova D, Verhaar MC, Evans RG, Russell DM, Joles JA, Malpas S (2012). Variation in kidney oxygenation: towards long‐term recording by telemetry. The FASEB Journal, 26(S1), 684.2-684.2.
2011
Wesseling SA, Essers PB, Koeners MP, Pereboom TC, Braam BA, MacInnes AW, Joles JA (2011). Perinatal Exogenous Nitric Oxide in Fawn-Hooded Hypertensive Rats That Persistently Lowers Blood Pressure in Adult Life Reduces Renal Ribosomal Biogenesis in Early Life.
Author URL.
Wesseling S, Essers PB, Koeners MP, Pereboom TC, Braam B, van Faassen EE, Macinnes AW, Joles JA (2011). Perinatal exogenous nitric oxide in fawn-hooded hypertensive rats reduces renal ribosomal biogenesis in early life.
Front Genet,
2Abstract:
Perinatal exogenous nitric oxide in fawn-hooded hypertensive rats reduces renal ribosomal biogenesis in early life.
Nitric oxide (NO) is known to depress ribosome biogenesis in vitro. In this study we analyzed the influence of exogenous NO on ribosome biogenesis in vivo using a proven antihypertensive model of perinatal NO administration in genetically hypertensive rats. Fawn-hooded hypertensive rat (FHH) dams were supplied with the NO-donor molsidomine in drinking water from 2 weeks before to 4 weeks after birth, and the kidneys were subsequently collected from 2 day, 2 week, and 9 to 10-month-old adult offspring. Although the NO-donor increased maternal NO metabolite excretion, the NO status of juvenile renal (and liver) tissue was unchanged as assayed by EPR spectroscopy of NO trapped with iron-dithiocarbamate complexes. Nevertheless, microarray analysis revealed marked differential up-regulation of renal ribosomal protein genes at 2 days and down-regulation at 2 weeks and in adult males. Such differential regulation of renal ribosomal protein genes was not observed in females. These changes were confirmed in males at 2 weeks by expression analysis of renal ribosomal protein L36a and by polysome profiling, which also revealed a down-regulation of ribosomes in females at that age. However, renal polysome profiles returned to normal in adults after early exposure to molsidomine. No direct effects of molsidomine were observed on cellular proliferation in kidneys at any age, and the changes induced by molsidomine in renal polysome profiles at 2 weeks were absent in the livers of the same rats. Our results suggest that the previously found prolonged antihypertensive effects of perinatal NO administration may be due to epigenetically programmed alterations in renal ribosome biogenesis during a critical fetal period of renal development, and provide a salient example of a drug-induced reduction of ribosome biogenesis that is accompanied by a beneficial long-term health effect in both males and females.
Abstract.
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Koeners MP, Braam B, Joles JA (2011). Perinatal inhibition of NF-kappaB has long-term antihypertensive effects in spontaneously hypertensive rats.
J Hypertens,
29(6), 1160-1166.
Abstract:
Perinatal inhibition of NF-kappaB has long-term antihypertensive effects in spontaneously hypertensive rats.
BACKGROUND: Excessive reactive oxygen species (ROS) activate the inflammatory transcription factor nuclear factor-kappa B (NF-κB). ROS-induced inflammation appears to be an early event in the development of hypertension in different models. In the spontaneously hypertensive rat (SHR) we investigated whether perinatal inhibition of NF-κB persistently decreases blood pressure. To probe antihypertensive mechanisms we studied natriuresis and sensitivity of blood pressure and renal hemodynamics to the superoxide dismutase mimetic Tempol. METHODS AND RESULTS: Perinatal pyrrolidine di thio carbamate (PDTC) (a NF-κB inhibitor), administered during pregnancy and lactation to SHR dams, persistently ameliorated hypertension up to 28 weeks of age in their offspring. Furthermore, after perinatal treatment with PDTC natriuresis was temporarily doubled at 4 weeks of age in both females and males. Urinary excretion of thiobarbituric acid reactive substances (an indirect measure of oxidative stress) was decreased by perinatal PDTC, persistently in females and temporarily in males. At 28 weeks, Tempol reduced arterial pressure in all groups, but had opposite effects in control and perinatal PDTC rats on renal vascular resistance (RVR), namely decreased RVR in controls and increased RVR in perinatal PDTC rats. CONCLUSION: These data indicate that increased activity of NF-κB very early in life, presumably in conjunction with oxidative stress, can lead to the development of hypertension. Perinatal inhibition of NF-κB has persistent antihypertensive effects. This could be related to a short phase of enhanced sodium excretion at an early age, and persistent changes of intrarenal vasoreactivity to ROS.
Abstract.
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Wesseling S, Koeners MP, Joles JA (2011). Salt sensitivity of blood pressure: developmental and sex-related effects.
Am J Clin Nutr,
94(6 Suppl), 1928S-1932S.
Abstract:
Salt sensitivity of blood pressure: developmental and sex-related effects.
Epidemiologic studies have shown convincingly that drastically reducing salt intake in the community is accompanied by blood pressure reductions that are comparable to those achieved by antihypertensive medication. Moreover, many subjects with hypertension are salt sensitive. This implies that, in these subjects, blood pressure is more responsive to changes in salt intake than in subjects with normal blood pressure. The presence of conventional risk factors associated with the metabolic syndrome correlates with salt sensitivity. However, women appear to be more salt sensitive than men. Sparse data indicate that the salt sensitivity of blood pressure is greater in subjects with low birth weight. Experimental studies in rats have also shown that hypertensive offspring of dams maintained on low-protein diets throughout or in late pregnancy are more salt sensitive. This is accompanied by increased expression of the thick ascending limb Na-K-2Cl symporter (NKCC2). Perinatal interventions aimed at persistently lowering blood pressure in genetically hypertensive rats have consistently proven to be very effective and are often accompanied by a wave of natriuresis exclusively at 4 wk of age. In sum, in addition to conventional metabolic risk factors for cardiovascular disease, low birth weight and possibly its sequels such as catch-up growth should be viewed as modifiable risk factors for salt sensitivity of blood pressure. Female sex may also be a nonmodifiable risk factor for salt sensitivity. Experimental data indicate that NKCC2 may well be an important determinant of salt sensitivity in acquired (developmental) hypertension.
Abstract.
Author URL.
Koeners MP, Wesseling S, Ulu A, Sepúlveda RL, Morisseau C, Braam B, Hammock BD, Joles JA (2011). Soluble epoxide hydrolase in the generation and maintenance of high blood pressure in spontaneously hypertensive rats.
Am J Physiol Endocrinol Metab,
300(4), E691-E698.
Abstract:
Soluble epoxide hydrolase in the generation and maintenance of high blood pressure in spontaneously hypertensive rats.
We hypothesized that perinatal inhibition of soluble epoxide hydrolase (SEH), which metabolizes epoxyeicosatrienoic acids in the arachidonic acid (AA) cascade, with an orally active SEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), would persistently reduce blood pressure (BP) in adult SHR despite discontinuation of AUDA at 4 wk of age. Renal cytoplasmic epoxide hydrolase-2 (Ephx2) gene expression was enhanced in SHR vs. WKY from 2 days to 24 wk. Effects of perinatal treatment with AUDA, supplied to SHR dams until 4 wk after birth, on BP in female and male offspring and renal oxylipin metabolome in female offspring were observed and contrasted to female SHR for direct effects of AUDA (8-12 wk). Briefly, inhibition of SEH was effective in persistently reducing BP in female SHR when applied during the perinatal phase. This was accompanied by marked increases in major renal AA epoxides and decreases in renal lipoxygenase products of AA. Early inhibition of SEH induced a delayed increase in renal 5-HETE at 24 wk, in contrast to a decrease at 2 wk. Inhibition of SEH in female SHR from 8 to 12 wk did not reduce BP but caused profound decreases in renal 15(S)-HETrE, LTB4, TBX2, 5-HETE, and 20-HETE and increases in TriHOMEs. In male SHR, BP reduction after perinatal AUDA was transient. Thus, Ephx2 transcription and SEH activity in early life may initiate mechanisms that eventually contribute to high BP in adult female SHR. However, programmed BP-lowering effects of perinatal SEH inhibition in female SHR cannot be simply explained by persistent reduction in renal SEH activity but rather by more complex and temporally dynamic interactions between the renal SEH, lipoxygenase, and cyclooxygenase pathways.
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2010
Koeners MP, Braam B, van der Giezen DM, Goldschmeding R, Joles JA (2010). Perinatal micronutrient supplements ameliorate hypertension and proteinuria in adult fawn-hooded hypertensive rats.
Am J Hypertens,
23(7), 802-808.
Abstract:
Perinatal micronutrient supplements ameliorate hypertension and proteinuria in adult fawn-hooded hypertensive rats.
BACKGROUND: in fawn-hooded hypertensive (FHH) rats, a model of hypertension, impaired preglomerular resistance, hyperfiltration, and progressive renal injury, we recently observed that supporting perinatal nitric oxide (NO) availability with the NO donor molsidomine persistently reduced blood pressure (BP) and ameliorated renal injury in male and female offspring. However, beneficial effects of perinatal molsidomine treatment were more pronounced in female than in male FHH rats. METHODS: to evaluate whether such protective effects could also be achieved with micronutrients, and whether the gender-dependent differences could be confirmed, we tested perinatal exposure to the micronutrients L-arginine, taurine, vitamin C, and vitamin E (ATCE) in FHH rats. Perinatal micronutrients increased urinary NO metabolite, sodium and potassium excretion only at 4 weeks of age, i.e. at the end of treatment. RESULTS: from 12 weeks onwards, control males had a significantly higher systolic BP (SBP) than females (P < 0.01); however after perinatal micronutrients, this difference was no longer present, indicating a pronounced antihypertensive effect of perinatal micronutrients in males (interaction P < 0.001). Development of proteinuria was attenuated by perinatal micronutrients in males and females. However, only females showed reduced glomerular filtration rate, filtration fraction, and glomerulosclerosis (GS) after perinatal micronutrients. CONCLUSIONS: in sum, perinatal micronutrients that enhance NO availability ameliorated development of hypertension and proteinuria in FHH rats. Antihypertensive effects were more pronounced in male FHH offspring, whereas renal protective effects were more pronounced in female FHH offspring. Mechanisms underlying gender-specific consequences of perinatal micronutrients require further study.
Abstract.
Author URL.
Gerritsen KG, Peters HP, Nguyen TQ, Koeners MP, Wetzels JF, Joles JA, Christensen EI, Verroust PJ, Li D, Oliver N, et al (2010). Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion.
Am J Physiol Renal Physiol,
298(6), F1457-F1464.
Abstract:
Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion.
Connective tissue growth factor (CTGF) plays a key role in renal fibrosis. Urinary CTGF is elevated in various renal diseases and may have biomarker potential. However, it is unknown which processes contribute to elevated urinary CTGF levels. Thus far, urinary CTGF was considered to reflect renal expression. We investigated how tubular dysfunction affects urinary CTGF levels. To study this, we administered recombinant CTGF intravenously to rodents. We used both full-length CTGF and the NH(2)-terminal fragment, since the NH(2)-fragment is the predominant form detected in urine. Renal CTGF extraction, determined by simultaneous arterial and renal vein sampling, was 18 +/- 3% for full-length CTGF and 21 +/- 1% for the NH(2)-fragment. Fractional excretion was very low for both CTGFs (0.02 +/- 0.006% and 0.10 +/- 0.02%, respectively), indicating that >99% of the extracted CTGF was metabolized by the kidney. Immunohistochemistry revealed extensive proximal tubular uptake of CTGF in apical endocytic vesicles and colocalization with megalin. Urinary CTGF was elevated in megalin- and cubilin-deficient mice but not in cubilin-deficient mice. Inhibition of tubular reabsorption by Gelofusine reduced renal uptake of CTGF and increased urinary CTGF. In healthy volunteers, Gelofusine also induced an increase of urinary CTGF excretion, comparable to the increase of beta(2)-microglobulin excretion (r = 0.99). Furthermore, urinary CTGF correlated with beta(2)-microglobulin (r = 0.85) in renal disease patients (n = 108), and only beta(2)-microglobulin emerged as an independent determinant of urinary CTGF. Thus filtered CTGF is normally reabsorbed almost completely in proximal tubules via megalin, and elevated urinary CTGF may largely reflect proximal tubular dysfunction.
Abstract.
Author URL.
2009
Wesseling S, Koeners MP, Kantouh F, Joles JA, Braam B (2009). Consequences of perinatal treatment with L-arginine and antioxidants for the renal transcriptome in spontaneously hypertensive rats.
Pflugers Arch,
458(3), 513-524.
Abstract:
Consequences of perinatal treatment with L-arginine and antioxidants for the renal transcriptome in spontaneously hypertensive rats.
Treating spontaneously hypertensive rats (SHR) with L-arginine, taurine, and vitamins C and E (ATCE) during nephrogenesis (2 weeks before to 4 weeks after birth) persistently lowers blood pressure. Hypothetically, differential gene expression in kidney of SHR vs. normotensive Wistar-Kyoto rats (WKY) is partially corrected by maternal ATCE in SHR. Differential gene expression in 2-days, 2-weeks, and 48-week-old rats was studied using oligonucleotide chips. Transcription factor binding sites (TFBS) of differentially expressed genes were analyzed in silico. Differential gene expression varied between SHR+ATCE and SHR, suggesting both direct and indirect effects; but, few genes were modulated toward WKY level and there was little overlap between ages. TFBS analysis suggests less Elk-1-driven gene transcription in both WKY and SHR+ATCE vs. SHR at 2 days and 2 weeks. Concluding, in SHR, persistent antihypertensive effects of maternal ATCE are not primarily due to persistent corrective transcription. Less Elk-1-driven transcription at 2 days and 2 weeks may be involved.
Abstract.
Author URL.
Wesseling S, Koeners MP, Braam B, Joles JA (2009). High Salt Dissociates Blood Pressure from Renal Injury in Female Fawn-Hooded Hypertensive Rats with and Without Perinatal Molsidomine Treatment.
Author URL.
Cupples W, Lau C, Obara R, Koeners M (2009). Reduction of heart rate, but not heart rate variability, in diabetic rats. The FASEB Journal, 23(S1), 1019.17-1019.17.
Wesseling S, Koeners MP, Joles JA (2009). Taurine: red bull or red herring?.
Hypertension,
53(6), 909-911.
Author URL.
2008
Koeners MP, Braam B, van der Giezen DM, Goldschmeding R, Joles JA (2008). A perinatal nitric oxide donor increases renal vascular resistance and ameliorates hypertension and glomerular injury in adult fawn-hooded hypertensive rats.
Am J Physiol Regul Integr Comp Physiol,
294(6), R1847-R1855.
Abstract:
A perinatal nitric oxide donor increases renal vascular resistance and ameliorates hypertension and glomerular injury in adult fawn-hooded hypertensive rats.
Enhancing perinatal nitric oxide (NO) availability persistently reduces blood pressure in spontaneously hypertensive rats. We hypothesize that this approach can be generalized to other models of genetic hypertension, for instance those associated with renal injury. Perinatal exposure to the NO donor molsidomine was studied in fawn-hooded hypertensive (FHH) rats, a model of mild hypertension, impaired preglomerular resistance, and progressive renal injury. Perinatal molsidomine increased urinary NO metabolite excretion at 8 wk of age, i.e. 4 wk after treatment was stopped (P < 0.05). Systolic blood pressure was persistently reduced after molsidomine (42-wk females: 118 +/- 3 vs. 141 +/- 5 and 36-wk males: 139 +/- 4 vs. 158 +/- 4 mmHg; both P < 0.001). Perinatal treatment decreased glomerular filtration rate (P < 0.05) and renal blood flow (P < 0.01) and increased renal vascular resistance (P < 0.05), without affecting filtration fraction, suggesting persistently increased preglomerular resistance. At 4 wk of age natriuresis was transiently increased by molsidomine (P < 0.05). Molsidomine decreased glomerulosclerosis (P < 0.05). Renal blood flow correlated positively with glomerulosclerosis in control (P < 0.001) but not in perinatally treated FHH rats. NO dependency of renal vascular resistance was increased by perinatal molsidomine. Perinatal enhancement of NO availability can ameliorate development of hypertension and renal injury in FHH rats. Paradoxically, glomerular protection by perinatal exposure to the NO donor molsidomine may be due to persistently increased preglomerular resistance. The mechanisms by which increased perinatal NO availability can persistently reprogram kidney function and ameliorate hypertension deserve further study.
Abstract.
Author URL.
Koeners MP, Braam B, Joles JA (2008). Blood pressure follows the kidney: Perinatal influences on hereditary hypertension.
Organogenesis,
4(3), 153-157.
Abstract:
Blood pressure follows the kidney: Perinatal influences on hereditary hypertension.
Epidemiological and experimental data strongly suggest that cardiovascular diseases can originate from an aberrant environment during fetal development, a phenomenon referred to as perinatal programming. This review will focus on the role of the kidneys in determining blood pressure, and how (re)programming the renal development can persistently ameliorate hereditary hypertension. By combining physiologic and genomic studies we have discovered some candidate pathways suited for (re)programming the development of hypertension. This sets the stage for mechanistic analysis in future studies.
Abstract.
Author URL.
van Faassen EE, Koeners MP, Joles JA, Vanin AF (2008). Detection of basal NO production in rat tissues using iron-dithiocarbamate complexes.
Nitric Oxide,
18(4), 279-286.
Abstract:
Detection of basal NO production in rat tissues using iron-dithiocarbamate complexes.
We probe endogenous NO production in WKY rats by trapping NO with iron-dithiocarbamate complexes. The aim was to detect non-stimulated NO production in small organs like kidneys of juvenile rats. The yields of mononitrosyl Fe-dithiocarbamate complexes are small and difficult to quantify in the presence of strong contaminating signals from Cu2+-DETC complexes. We evaluate four methods to improve the detection of mononitrosyl Fe-dithiocarbamate adducts: progressive microwave saturation, tissue perfusion, spectral subtraction, and finally, reduction of the tissue with sodium dithionite. While the first three were only moderately useful, reduction was very helpful for quantification of the mononitrosyl Fe-dithiocarbamate yield. The increase in sensitivity allows the detection of non-stimulated NO release in small organs of juvenile rats.
Abstract.
Author URL.
2007
Koeners MP, Joles JA (2007). A fat chance of renal injury.
Kidney Int,
72(3), 232-234.
Abstract:
A fat chance of renal injury.
Williams et al. demonstrate in sheep that juvenile obesity per se leads to renal pathology but that prenatal undernutrition effectively abolishes any renal pathology associated with juvenile obesity. These peculiar findings are quite opposite to what has been documented in many epidemiological and animal studies. They provoke questions about how adverse developmental conditions can either support or compromise adaptation to excess nutrient intake and low motor activity later in life.
Abstract.
Author URL.
Koeners MP, van Faassen EE, Wesseling S, de Sain-van der Velden M, Koomans HA, Braam B, Joles JA (2007). Maternal supplementation with citrulline increases renal nitric oxide in young spontaneously hypertensive rats and has long-term antihypertensive effects.
Hypertension,
50(6), 1077-1084.
Abstract:
Maternal supplementation with citrulline increases renal nitric oxide in young spontaneously hypertensive rats and has long-term antihypertensive effects.
NO deficiency is associated with development of hypertension. Defects in the renal citrulline-arginine pathway or arginine reabsorption potentially reduce renal NO in prehypertensive spontaneously hypertensive rats (SHRs). Hence, we investigated genes related to the citrulline-arginine pathway or arginine reabsorption, amino acid pools, and renal NO in 2-week-old prehypertensive SHRs. In addition, because perinatally supporting NO availability reduces blood pressure in SHRs, we supplemented SHR dams during pregnancy and lactation with citrulline, the rate-limiting amino acid for arginine synthesis. In female offspring, gene expression of argininosuccinate synthase (involved in renal arginine synthesis) and renal cationic amino acid Y-transporter (involved in arginine reabsorption) were both decreased in 2-day and 2-week SHRs compared with normotensive WKY, although no abnormalities in amino acid pools were observed. In addition, 2-week-old female SHRs had much less NO in their kidneys (0.46+/-0.01 versus 0.68+/-0.05 nmol/g of kidney weight, respectively; P
Abstract.
Author URL.
Koeners MP, Racasan S, Koomans HA, Joles JA, Braam B (2007). Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L-arginine and antioxidants.
ACTA PHYSIOLOGICA,
190(4), 329-338.
Author URL.
Koeners MP, Racasan S, Koomans HA, Joles JA, Braam B (2007). Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L-arginine and antioxidants.
Acta Physiol (Oxf),
190(4), 329-338.
Abstract:
Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L-arginine and antioxidants.
AIM: Nitric oxide (NO) and superoxide are considered to be regulatory in renal blood flow (RBF) autoregulation, and hence may contribute to development of hypertension. To extend our previous observations that dynamic NO release is impaired in the spontaneously hypertensive rat (SHR) we investigated, firstly, if superoxide dependency of RBF autoregulation is increased in SHR and, secondly, if the beneficial effect of perinatal supplementation in SHR is partly as a result of early correction of RBF autoregulation. We hypothesized that perinatal supplementation by restoring dynamic NO release and/or decreasing superoxide dependency and would improve life-long blood pressure regulation. METHODS: Autoregulation was studied using stepwise reductions in renal perfusion pressure in anaesthetized male SHR, SHR perinatally supplemented with arginine and antioxidants (SHRsuppl) and Wistar-Kyoto (WKY), prior to and during i.v. Nomega-nitro-l-arginine (NO synthase inhibitor) or tempol (superoxide dismutase mimetic). RESULTS: Spontaneously hypertensive rat displayed a wider operating range of RBF autoregulation as compared with WKY (59 +/- 4 vs. 33 +/- 2 mmHg, respectively; P < 0.01). Perinatal supplementation in SHR decreased mean arterial pressure, renal vascular resistance and the operating range of RBF autoregulation (43 +/- 3 mmHg; P < 0.01). In addition autoregulation efficiency decreased. RBF autoregulation characteristics shifted towards those of normotensive WKY. However, dynamic NO release was still impaired and no clear differences in superoxide dependency in RBF autoregulation between groups was observed. CONCLUSION: Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long-term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation.
Abstract.
Author URL.
Wesseling S, Joles JA, Koeners MP, Koomans HA (2007). The renal transcriptome in spontaneously hypertensive rats from birth to old age: the search for transcription factor candidates for each phase of development.
Author URL.
2006
Koeners MP, Braam B, Koomans HA, Goldschmeding R, Joles JA (2006). Long-term effects of perinatal nitric oxide supplementation on blood pressure and glomerulosclerosis in fawn-hooded hypertensive rats.
Author URL.
Koeners MP, Braam B, Koomans HA, van der Giezen DM, Goldschmeding R, Joles JA (2006). Long-term effects on blood pressure and renal function in fawn-hooded hypertensive rats (FHH) after perinatal treatment supporting nitric oxide (NO) availability.
Author URL.
2005
Hillebrand JJG, Koeners MP, de Rijke CE, Kas MJH, Adan RAH (2005). Leptin treatment in activity-based anorexia.
Biol Psychiatry,
58(2), 165-171.
Abstract:
Leptin treatment in activity-based anorexia.
BACKGROUND: Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa (AN). In ABA, scheduled feeding together with voluntary access to a running wheel results in increased running wheel activity (RWA), hypophagia, and body weight loss. Previously it was shown that leptin treatment reduced semi-starvation-induced hyperactivity in rats. The present study was performed to confirm and extend this finding, to evaluate leptin's effect on energy balance in ABA. METHODS: the effects of chronic leptin treatment (intracerebroventricular, 4 microg/day) in ABA rats, ad libitum-fed running rats, and sedentary rats exposed to ad libitum feeding or scheduled feeding were investigated. RESULTS: Leptin treatment decreased RWA in ABA rats. Additionally, leptin treatment reduced food intake and increased energy expenditure by thermogenesis in ABA rats. Ad libitum-fed running/sedentary rats or food-restricted sedentary rats did not reduce activity after leptin treatment, whereas all leptin-treated rats showed hypophagia. Body temperature was slightly increased in leptin-treated food-restricted sedentary rats. CONCLUSIONS: Although leptin treatment reduced RWA in ABA rats, it also prevented hypothermia and decreased food intake. Altogether, this resulted in a stronger negative energy balance and body weight loss in leptin-treated ABA rats.
Abstract.
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2003
Adan RAH, Hillebrand J, Van Elburg A, Koeners M, Van Engeland H, Kas MJH (2003). S.10.01 Animal models for eating disorders. European Neuropsychopharmacology, 13, s119-s120.
2002
Racasan S, Koeners MP, Koomans HA, Joles JA, Braam B (2002). Perinatal treatment with antioxidants reduces blood pressure in adult SHR.
Author URL.