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Pflügers Archiv - European Journal of Physiology 11/2012; · 4.46 Impact Factor
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David Penton,
Sascha Bandulik, Frank Schweda,
Sophia Haubs,
Philipp Tauber,
Markus Reichold,
Lu Dang Cong,
Abeer El Wakil,
Thomas Budde,
Florian Lesage,
Enzo Lalli,
Maria-Christina Zennaro,
Richard Warth,
Jacques Barhanin
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ABSTRACT: Task1 and Task3 potassium channels (Task: tandem of P domains in a weak inward rectifying K(+) channel-related acid-sensitive K(+) channel) are believed to control the membrane voltage of aldosterone-producing adrenal glomerulosa cells. This study aimed at understanding the role of Task3 for the control of aldosterone secretion. The adrenal phenotype of Task3(-/-) mice was investigated using electrophysiology, adrenal slices, and blood pressure measurements. Primary adrenocortical cells of Task3(-/-) mice were strongly depolarized compared with wild-type (-52 vs. -79 mV), and in fresh adrenal slices Ca(2+) signaling of Task3(-/-) glomerulosa cells was abnormal. In living Task3(-/-) mice, the regulation of aldosterone secretion showed specific deficits: Under low Na(+) and high K(+) diets, protocols known to increase aldosterone, and under standard diet, Task3 inactivation was compensated and aldosterone was normal. However, high Na(+) and low K(+) diets, two protocols known to lower aldosterone, failed to lower aldosterone in Task3(-/-) mice. The physiological regulation of aldosterone was disturbed: aldosterone-renin ratio, an indicator of autonomous aldosterone secretion, was 3-fold elevated at standard and high Na(+) diets. Isolated adrenal glands of Task3(-/-) produced 2-fold more aldosterone. As a consequence, Task3(-/-) mice showed salt-sensitive arterial hypertension (plus 10 mm Hg). In conclusion, Task3 plays an important role in the adaptation of aldosterone secretion to dietary salt intake.
Endocrinology 08/2012; 153(10):4740-8. · 4.46 Impact Factor
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ABSTRACT: Severe sepsis is often accompanied by acute renal failure with renal tubular dysfunction. Albuminuria is a common finding in septic patients and we studied whether it was due to an impairment of proximal tubular endocytosis of filtered albumin. We studied the regulation of megalin and cubilin, the two critical multiligand receptors responsible for albumin absorption, during severe experimental endotoxemia. Lipopolysaccharide (LPS) caused a time- and dose-dependent suppression of megalin and cubilin expression that was paralleled by a decrease in plasma albumin levels and an increase in the urine concentration of albumin in mice. Incubation of rat renal cortical slices with LPS also reduced the mRNA expression of megalin and cubilin. Further, LPS suppressed megalin and cubilin mRNA expression in murine primary proximal tubule cells and decreased the uptake of FITC albumin in these cells. In addition, the increase in urine levels of albumin in response to ischemia/reperfusion-induced acute renal failure was paralleled by a decrease in the expression of megalin and cubilin. Thus, our data indicate that the expression of megalin and cubilin is decreased during experimental endotoxemia and in response to renal ischemia/reperfusion injury. This downregulation may contribute, in part, to an increase in urine levels of albumin during acute renal failure.
Kidney International 03/2012; 82(1):53-9. · 6.61 Impact Factor
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ABSTRACT: Proteinase-activated receptors (PARs) 1 to 4 are highly expressed in the kidney and are involved in the regulation of renal hemodynamics and tubular function. Since intravascular infusion of the proteinase thrombin, which activates PARs, has been shown to decrease plasma renin activity in rats, we investigated the effects of the respective PAR subtypes on renin release using the isolated perfused mouse kidney model. Thrombin dose-dependently reduced perfusate flow and inhibited renin secretion rates (RSRs) that had been prestimulated by the β-adrenoreceptor agonist isoproterenol. The suppression of RSRs was prevented by the selective PAR1 inhibitor SCH79797, and direct activation of PAR1 by TFLLR mimicked the effects of thrombin on RSRs and vascular tone. Moreover, TFLLR suppressed the stimulations of RSRs in response to the loop diuretic bumetanide, to prostaglandin E(2), or to a decrease in renal perfusion pressure but not in response to a reduction in extracellular calcium. The PAR2-activating peptide SLIGRL concentration dependently increased RSR and perfusate flow. The stimulation of RSRs by SLIGRL was markedly attenuated by N(G)-nitro-L-arginine methyl ester, suggesting an NO-dependent mechanism. Activation of PAR4 by AYPGKF did not modulate RSRs or perfusate flow. PAR1 and PAR2 immunoreactivity were detected in the juxtaglomerular region and were colocalized with renin immunoreactivity. Our data provide evidence that PAR1 activation inhibits renal renin secretion and induces renal vasoconstriction, whereas PAR2 activation stimulates renin release and induces vasodilation mainly via the release of NO.
Hypertension 08/2011; 58(4):611-8. · 6.21 Impact Factor
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ABSTRACT: Deletion of the gap-junction-forming protein connexin40 leads to renin-dependent hypertension in mice, but whether observed human variants in connexin40, such as A96S, promote hypertension is unknown. Here, we generated mice with the A96S variant in the mouse connexin40 gene. Although mice homozygous for the A96S mutations had normal expression patterns of connexin40 in the kidney, they were hypertensive, had sixfold higher plasma renin concentrations, and had 40% higher levels of renin mRNA than controls. Renin-expressing cells were aberrantly located outside the media layer of afferent arterioles, and increased renal perfusion pressure did not inhibit renin secretion from kidneys isolated from homozygous A96S mice. Treatment with a low-salt diet in combination with an ACE inhibitor increased renin mRNA levels, plasma renin concentrations, and the number of aberrantly localized renin-producing cells. Taken together, these findings suggest that the A96S mutation in connexin40 leads to renin-dependent hypertension in mice. Modulation of renin secretion by BP critically depends on functional connexin40; with the A96S mutation, the aberrant extravascular localization of renin-secreting cells in the kidney likely impairs the pressure-mediated inhibition of renin secretion.
Journal of the American Society of Nephrology 06/2011; 22(6):1031-40. · 9.66 Impact Factor
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ABSTRACT: The sympathetic nervous system stimulates renin release from juxtaglomerular cells via the β-adrenoreceptor-cAMP pathway. Recent in vitro studies have suggested that the calcium-inhibited adenylyl cyclases (ACs) 5 and 6 possess key roles in the control of renin exocytosis. To investigate the relative contribution of AC5 and AC6 to the regulation of renin release in vivo we performed experiments using AC5 and AC6 knockout mice. Male AC5(-/-) mice exhibited normal plasma renin concentrations, renal renin synthesis (mRNA and renin content), urinary volume, and systolic blood pressure. In male AC6(-/-) mice, plasma renin concentration (AC6(-/-): 732 ± 119; AC6 (+/+): 436 ± 78 ng of angiotensin I per hour*mL(-1); P<0.05), and renin synthesis were stimulated associated with an increased excretion of dilute urine (1.55-fold; P<0.05) and reduced blood pressure (-10.6 mm Hg; P<0.001). Stimulation of plasma renin concentration by a single injection of the β-adrenoreceptor agonist isoproterenol (10 mg/kg IP) was significantly attenuated in AC5(-/-) (male: -20%; female: -33%) compared with wild-type mice in vivo. The mitigation of the plasma renin concentration response to isoproterenol was even more pronounced in AC6(-/-) (male: -63%; female: -50% versus AC6(+/+)). Similarly, the effects of isoproterenol, prostaglandin E2, and pituitary adenylyl cyclase-activating polypeptide on renin release from isolated perfused kidneys were attenuated to a higher extent in AC6(-/-) (-51% to -98% versus AC6(+/+)) than in AC5(-/-) (-31% to 46% versus AC5(+/+)). In conclusion, both AC5 and AC6 are involved in the stimulation of renin secretion in vivo, and AC6 is the dominant isoforms in this process.
Hypertension 03/2011; 57(3):460-8. · 6.21 Impact Factor
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Ralf Hausmann,
Christoph Kuppe,
Herbert Egger, Frank Schweda,
Volker Knecht,
Marlies Elger,
Sylvia Menzel,
Douglas Somers,
Gerald Braun,
Astrid Fuss,
Sandra Uhlig,
Wilhelm Kriz,
George Tanner,
Jürgen Floege,
Marcus J Moeller
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ABSTRACT: There is ongoing controversy about the mechanisms that determine the characteristics of the glomerular filter. Here, we tested whether flow across the glomerular filter generates extracellular electrical potential differences, which could be an important determinant of glomerular filtration. In micropuncture experiments in Necturus maculosus, we measured a potential difference across the glomerular filtration barrier that was proportional to filtration pressure (-0.045 mV/10 cm H₂O). The filtration-dependent potential was generated without temporal delay and was negative within Bowman's space. Perfusion with the cationic polymer protamine abolished the potential difference. We propose a mathematical model that considers the relative contributions of diffusion, convection, and electrophoretic effects on the total flux of albumin across the filter. According to this model, potential differences of -0.02 to -0.05 mV can induce electrophoretic effects that significantly influence the glomerular sieving coefficient of albumin. This model of glomerular filtration has the potential to provide a mechanistic theory, based on experimental data, about the filtration characteristics of the glomerular filtration barrier. It provides a unique approach to the microanatomy of the glomerulus, renal autoregulation, and the pathogenesis of proteinuria.
Journal of the American Society of Nephrology 12/2010; 21(12):2053-8. · 9.66 Impact Factor
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ABSTRACT: Renin-producing juxtaglomerular cells are connected to each other and to endothelial cells of afferent arterioles by gap junctions containing Connexin 40 (Cx40), abundantly expressed by these two cell types. Here, we generated mice with cell-specific deletion of Cx40 in endothelial and in renin-producing cells, as its global deletion caused local dissociation of renin-producing cells from endothelial cells, renin hypersecretion, and hypertension. In mice lacking endothelial Cx40, the blood pressure, renin-producing cell distribution, and the control of renin secretion were similar to wild-type mice. In contrast, mice deficient for Cx40 in renin-producing cells were hypertensive and these cells were ectopically localized. Although plasma renin activity and kidney renin mRNA levels of these mice were not different from controls, the negative regulation of renin secretion by pressure was inverted to a positive feedback in kidneys lacking Cx40 in renin-producing cells. Thus, our findings show that endothelial Cx40 is not essential for the control of renin expression and/or release. Cx40 in renin-producing cells is required for their correct positioning in the juxtaglomerular area and the control of renin secretion by pressure.
Kidney International 10/2010; 78(8):762-8. · 6.61 Impact Factor
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ABSTRACT: The retina expresses a local renin-angiotensin system (RAS). This study aimed to investigate the influence of systemic modulation of renin synthesis on the expression of renin in the retinal pigment epithelium (RPE), which forms part of the blood/retina barrier. Freshly isolated RPE cells showed expression of renin 1A, which is the secreted isoform of renin. Systemic administration of the angiotensin-converting enzyme inhibitor enalapril in mice increased the renin expression in both the kidney and the retina. Systemic infusion of ANG II led to a decrease in the renin expression in the kidney and in the retina and RPE. The ANG II-dependent down-regulation of renin expression in the RPE was prevented by systemic application of the AT(1) receptor blocker losartan. However, water deprivation lead to an increase of the renin expression in the kidney but unexpectedly to a decrease of the renin expression in the retina. In sections of the mouse retina, the ANG II receptor AT(1) was found in the RPE and localized at the blood side of the epithelium. Short-time cultured RPE cells showed increases in intracellular free Ca(2+) in response to stimulation by ANG II that were sensitive to losartan. In summary, we conclude that the renin expression in cells of the blood/retina barrier is influenced by the systemic RAS. ANG II circulating in the plasma is likely a mediator of this influence.
AJP Renal Physiology 08/2010; 299(2):F396-403. · 4.42 Impact Factor
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ABSTRACT: The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca(2+) (inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-(1-7).
Physiological Reviews 04/2010; 90(2):607-73. · 26.87 Impact Factor
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ABSTRACT: The angiotensin receptor-associated protein (Atrap) interacts with angiotensin II (AngII) type 1 (AT1) receptors and facilitates their internalization in vitro, but little is known about the function of Atrap in vivo. Here, we detected Atrap expression in several organs of wild-type mice; the highest expression was in the kidney where it localized to the proximal tubule, particularly the brush border. There was no Atrap expression in the renal vasculature or juxtaglomerular cells. We generated Atrap-deficient (Atrap-/-) mice, which were viable and seemed grossly normal. Mean systolic BP was significantly higher in Atrap-/- mice compared with wild-type mice. Dose-response relationships of arterial BP after acute AngII infusion were similar in both genotypes. Plasma volume was significantly higher and plasma renin concentration was markedly lower in Atrap-/- mice compared with wild-type mice. (125)I-AngII binding showed enhanced surface expression of AT1 receptors in the renal cortex of Atrap-/- mice, accompanied by increased carboanhydrase-sensitive proximal tubular function. In summary, Atrap-/- mice have increased arterial pressure and plasma volume. Atrap seems to modulate volume status by acting as a negative regulator of AT1 receptors in the renal tubules.
Journal of the American Society of Nephrology 03/2010; 21(3):468-77. · 9.66 Impact Factor
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ABSTRACT: We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)gamma stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARgamma. The mouse renin gene is regulated by PPARgamma through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPARgamma knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPARgamma would upregulate mouse renin expression. Consistent with these observations knockdown of PPARgamma increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPARgamma on renin production in vivo, we used a cre/lox system to generate double-transgenic mice with disrupted PPARgamma locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPARgamma(fl/fl) mice). We provide evidence that PPARgamma expression was effectively reduced in JG cells of RC-PPARgamma(fl/fl) mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPARgamma(fl/fl) than in littermate control RC-PPARgamma(wt/wt) mice. Renin mRNA levels and plasma renin concentration in RC-PPARgamma(fl/fl) mice were almost 2-fold higher than in littermate controls. Arterial blood pressure and pressure control of renal vascular resistance, which play decisive roles in the regulation of renin production were indistinguishable between RC-PPARgamma(wt/wt) and RC-PPARgamma(fl/fl) mice. These data demonstrate that the JG-specific PPARgamma deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPARgamma appears to be a relevant transcription factor for the control of renin gene in JG cells.
Hypertension 03/2010; 55(3):660-6. · 6.21 Impact Factor
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ABSTRACT: Fibrocytes are collagen-type-I-producing cells that arise at low frequency from hematopoietic cells. We have analyzed in mice which leukocyte subsets are required for generation of fibrocytes and show that murine fibrocytes develop from the subpopulation of CD11b(+) CD115(+) Gr1(+) monocytes under the control of CD4(+) T cells. In the absence of CD4(+) T cells, differentiation of fibrocytes was markedly reduced in vitro and in vivo. In the presence of CD4(+) T cells, the characteristics of T-cell activation critically determined development of fibrocytes. Polyclonal activation of CD4(+) T cells induced the release of soluble factors that completely prevented the outgrowth of fibrocytes and could be identified as IL-2, TNF, IFN-gamma, and IL-4. Application of IL-2 and TNF significantly reduced the appearance of fibrocytes and the severity of fibrosis in the model of unilateral ureteral obstruction. In contrast, activation of CD4(+) T cells in the presence of calcineurin inhibitors, but not mTOR inhibitors, markedly enhanced the outgrowth of fibrocytes and renal deposition of collagen I. Taken together, we show that differentiation of fibrocytes is critically dependent on CD4(+) T cells and that the context of T-cell activation determines whether development of fibrocytes is supported or blocked. Our data may have implications for prevention of organ fibrosis in autoimmune diseases and transplantation.
Proceedings of the National Academy of Sciences 10/2009; 106(42):17892-7. · 9.68 Impact Factor
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ABSTRACT: The influence of pantoprazole 40 mg twice daily on the bioavailability of a single dose of mycophenolate mofetil 1000 mg or enteric-coated mycophenolate sodium is investigated in healthy volunteers. The plasma concentrations of mycophenolic acid and of the inactive metabolite mycophenolic acid glucuronide are measured by high-performance liquid chromatography. The pharmacokinetic parameters following sole administration are similar for mycophenolate mofetil and enteric-coated mycophenolate sodium except for the time to peak concentration, which is longer in the enteric-coated mycophenolate sodium group. Concomitant treatment with pantoprazole significantly (P < .001) lowers the mycophenolic acid exposure following administration of mycophenolate mofetil. The peak concentrations drop by 57%, and area under the curve decreases from 0 to 12 hours by 27%. In contrast, pantoprazole does not change the pharmacokinetics of enteric-coated mycophenolate sodium. Given that mycophenolic acid exposure correlates with the incidence of biopsy-proven acute rejections in renal transplant recipients, these findings may have clinical implications. Administration of pantoprazole in combination with mycophenolate mofetil could possibly result in an insufficient mycophenolic acid exposure, increasing the risk of treatment failure.
The Journal of Clinical Pharmacology 10/2009; 49(10):1196-201. · 2.91 Impact Factor
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ABSTRACT: Within the juxtaglomerular apparatus, renin-producing cells and endothelial cells of the afferent arterioles express connexin (Cx)37 and Cx40, which form abundant gap junctions among these cells. Deletion of Cx40 leads to strong hyperreninemia and ectopic localization of renin-producing cells; however, the relevance of Cx37 for the renin system in the kidney has not been investigated. We therefore studied renin expression and renin secretion in kidneys from Cx37-deficient mice, both on normal salt diet and during chronic challenge of the renin system by pretreatment of mice with a low-salt diet in combination with an angiotensin I-converting enzyme inhibitor. This treatment procedure strongly enhances renin gene expression and renin secretion. We found that renal renin mRNA abundance and plasma renin concentration did not differ between wild-type and Cx37-/- mice under normal conditions. The stimulation of renin gene expression and renin secretion by salt depletion was even more pronounced in Cx37-/- as compared to wild-type mice. The regulation of renin secretion from isolated perfused kidneys by perfusion pressure and by angiotensin II was normal in Cx37-/- mice. In addition, the localization of renin-expressing cells was also regular in Cx37-/- kidneys. Finally, the expression pattern of other vascular Cxs such as Cx40, Cx43, and Cx45 was not altered in Cx37-/- kidneys. Our findings suggest that Cx37 is not essential for normal development and function of renin-producing cells. As a consequence, it appears unlikely that Cx40 exerts its important function in renin-producing cells via Cx37/Cx40 heteromeric gap junctions.
Pflügers Archiv - European Journal of Physiology 09/2009; 459(1):151-8. · 4.46 Impact Factor
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ABSTRACT: Connexins (Cxs) are a family of transmembrane proteins that form gap junctions with unique and redundant biophysical functions. Juxtaglomerular cells express Cx40, which is crucial to the control of renin secretion by blood pressure and angiotensin II, and mice that lack Cx40 have high plasma renin and hypertension. To examine whether normal juxtaglomerular cell function depends on the unique properties of Cx40, we measured renin release in mice where the coding sequence for Cx40 was replaced by that for Cx45, using the knock-in method. We first found that the knock-in strategy indeed resulted in expression of Cx45 but not Cx40 in the juxtaglomerular cells of these mice. The plasma renin concentration of the knock-in mice was similar to that in wild-type mice. The high blood pressure of the Cx40 knockout mice was significantly reduced when Cx45 was knocked into the locus but remained mildly elevated compared to wild-type mice. Blockade of angiotensin II formation by enalapril increased the plasma renin concentration in wild-type and the Cx45 knock-in mice but not in the Cx40 knockout mice. Infusion of angiotensin II into isolated perfused kidneys results in decreased renin release, a phenomenon that was attenuated in the Cx40 knockout mice. However, in the Cx45 knock-in mice, angiotensin II suppressed renin release similar to its effect in wild type mice. Unilateral renal artery stenosis increased the plasma renin concentration and blood pressure in both the wild-type and the Cx45 knock-in mice but not in the Cx40 knockout mice. Since Cx40 can be replaced by Cx45, a connexin with a significantly lower conductivity, we suggest that the regulation of renin release is not dependent on the unique electrical properties of these channel proteins.
Kidney International 01/2009; 75(5):482-9. · 6.61 Impact Factor
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Dirk Heitzmann,
Renaud Derand,
Stefan Jungbauer,
Sascha Bandulik,
Christina Sterner, Frank Schweda,
Abeer El Wakil,
Enzo Lalli,
Nicolas Guy,
Raymond Mengual,
Markus Reichold,
Ines Tegtmeier,
Saïd Bendahhou,
Celso E Gomez-Sanchez,
M Isabel Aller,
William Wisden,
Achim Weber,
Florian Lesage,
Richard Warth,
Jacques Barhanin
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ABSTRACT: TASK1 (KCNK3) and TASK3 (KCNK9) are two-pore domain potassium channels highly expressed in adrenal glands. TASK1/TASK3 heterodimers are believed to contribute to the background conductance whose inhibition by angiotensin II stimulates aldosterone secretion. We used task1-/- mice to analyze the role of this channel in adrenal gland function. Task1-/- exhibited severe hyperaldosteronism independent of salt intake, hypokalemia, and arterial 'low-renin' hypertension. The hyperaldosteronism was fully remediable by glucocorticoids. The aldosterone phenotype was caused by an adrenocortical zonation defect. Aldosterone synthase was absent in the outer cortex normally corresponding to the zona glomerulosa, but abundant in the reticulo-fasciculata zone. The impaired mineralocorticoid homeostasis and zonation were independent of the sex in young mice, but were restricted to females in adults. Patch-clamp experiments on adrenal cells suggest that task3 and other K+ channels compensate for the task1 absence. Adrenal zonation appears as a dynamic process that even can take place in adulthood. The striking changes in the adrenocortical architecture in task1-/- mice are the first demonstration of the causative role of a potassium channel in development/differentiation.
The EMBO Journal 02/2008; 27(1):179-87. · 9.20 Impact Factor
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ABSTRACT: The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in salt, volume, and blood pressure homeostasis of the body. Renin is mainly produced and released into circulation by the so-called juxtaglomerular epithelioid cells, located in the walls of renal afferent arterioles at the entrance of the glomerular capillary network. It has been known for a long time that renin synthesis and secretion are stimulated by the sympathetic nerves and the prostaglandins and are inhibited in negative feedback loops by angiotensin II, high blood pressure, salt, and volume overload. In contrast, the events controlling the function of renin-secreting cells at the organ and cellular level are markedly less clear and remain mysterious in certain aspects. The unravelling of these mysteries has led to new and interesting insights into the process of renin release.
Physiology (Bethesda, Md.) 11/2007; 22:310-9. · 7.95 Impact Factor
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ABSTRACT: Sepsis is the most important trigger for acute renal failure, with tubular dysfunction and collapse in urine concentration. As chloride plays a major role in the urinary concentrating mechanisms, we aimed to investigate the regulation of renal chloride entry pathways, such as kidney-specific chloride channel 1, kidney-specific chloride channel 2, Barttin, thiazide-sensitive Na+-Cl- cotransporter, renal outer medullary potassium channel, and Na+/K+-adenosine triphosphatase during sepsis.
Prospective animal trial.
Laboratory of the Department of Anesthesiology.
Male C57/BL6 and B6129SF2/J mice and mice deficient for tumor necrosis factor-alpha, interleukin-1-receptor-1, interferon-gamma, or interleukin-6.
Mice were injected with lipopolysaccharide (LPS) or proinflammatory cytokines. Hemodynamic and renal variables, cytokine concentrations, and expression of renal chloride-reabsorbing systems were investigated. Experiments with cytokine knockout mice, renal artery-clipped mice, and mice treated with glucocorticoids, low-dose LPS, and sodium nitroprusside were performed.
LPS-injected mice presented with decreased blood pressure and glomerular filtration rate, increased fractional chloride excretion, and depressed expression of renal chloride transporters/channels. Similar alterations were observed after application of tumor necrosis factor-alpha, interleukin-1beta, interferon-gamma, or interleukin-6. LPS-induced down-regulation of chloride transporters/channels was not affected in cytokine knockout mice. Glucocorticoid treatment inhibited LPS-induced increase of cytokine concentrations, diminished LPS-induced renal dysfunction, and attenuated the down-regulation of renal chloride transporters/channels. Injection of low-dose LPS increased renal tissue cytokines and down-regulated chloride entry pathways without arterial hypotension, indicating that renal ischemia due to systemic hypotension does not mediate down-regulation of renal chloride transporters/channels. In addition, renal ischemia induced by renal artery clipping or sodium nitroprusside administration did not influence chloride transporter/channel expression.
Our results demonstrate down-regulation of renal chloride transporters/channels during sepsis, which is probably mediated by proinflammatory cytokines and accounts for the development of LPS-induced tubular dysfunction. Our findings contribute to the understanding, on one hand, the failure of single-anticytokine strategies and, on the other hand, the beneficial effects of glucocorticoids in the therapy of septic patients.
Critical Care Medicine 10/2007; 35(9):2110-9. · 6.33 Impact Factor
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ABSTRACT: In the adult kidney, renin-producing cells are typically located in the walls of afferent arterioles at the transition into the glomerular capillary network. The mechanisms that are responsible for restricting renin expression to the juxtaglomerular position are largely unknown. This study showed that in mice that lack connexin 40 (Cx40), the predominant connexin of renin-producing cells, renin-positive cells are absent in the vessel walls and instead are found in cells of the extraglomerular mesangium, glomerular tuft, and periglomerular interstitium. Blocking macula densa transport function by acute administration of loop diuretics strongly enhances renin secretion in vivo and in isolated perfused kidneys of wild-type mice. This effect of loop diuretics is markedly attenuated in vivo and even blunted in vitro in Cx40-deficient mice. Even after prolonged stimulation of renin secretion by severe sodium depletion, renin expression is not seen in juxtaglomerular cells or in cells of more proximal parts of the arterial vessel wall as occurs normally. Instead, renin remains restricted to the extra-/periglomerular interstitium in Cx40-deficient mice. In contrast to the striking displacement of renin-expressing cells in the adult kidney, renin expression in the vessels of the developing kidney was found to be normal. This is the first evidence to indicate that cell-to-cell communication via gap junctions is essential for the correct juxtaglomerular positioning and recruitment of renin-producing cells. Moreover, these findings support the notion that gap junctions are relevant for the macula densa signaling to renin-producing cells.
Journal of the American Society of Nephrology 05/2007; 18(4):1103-11. · 9.66 Impact Factor
