Control Of Sodium Reabsorption Research Articles

NOX4-dependent regulation of ENaC in hypertension and diabetic kidney disease.

NADPH oxidase 4 (NOX4) is the most abundant NOX isoform in the kidney; however, its importance for renal function has only recently emerged. The NOX4-dependent pathway regulates many factors essential for proper sodium handling in the distal nephron. However, the functional significance of this pathway in the control of sodium reabsorption during the initiation of chronic kidney disease is not established. The goal of this study was to test Nox4-dependent ENaC regulation in two models: SS hypertension and STZ-induced type 1 diabetes. First, we showed that genetic ablation of Nox4 in Dahl salt-sensitive (SS) rat attenuated a high-salt (HS)-induced increase in epithelial Na+ channel (ENaC) activity in the cortical collecting duct. We also found that H2 O2 upregulated ENaC activity, and H2 O2 production was reduced in both the renal cortex and medulla in SSNox4-/- rats fed an HS diet. Second, in the streptozotocin model of hyperglycemia-induced renal injury ENaC activity in hyperglycemic animals was elevated in SS but not SSNox4-/- rats. NaCl cotransporter (NCC) expression was increased compared to healthy controls, while expression values between SS and SSNox4-/- groups were similar. These data emphasize a critical contribution of the NOX4-mediated pathway in maladaptive upregulation of ENaC-mediated sodium reabsorption in the distal nephron in the conditions of HS- and hyperglycemia-induced kidney injury.

Contribution of Kir4.1/Kir5.1 Channels to the Control of ENaC‐Mediated Apical Sodium Transport in the Cortical Collecting Duct

Recent studies using genetically modified animal models reveal that inwardly rectifying potassium channels Kir4.1 and Kir5.1, encoded by Kcnj10 and Kcnj16 genes, play an essential role in determining plasma potassium level and regulating blood pressure. Moreover, we have revealed recently that the deletion of Kcnj16 gene in Dahl salt‐sensitive (SS) rats has the profound effect on the blood pressure and renal damage. These data uncover a new potential target for the treatment of salt‐induced hypertension. Protein products of Kcnj10 and Kcnj16 are localized to the basolateral membrane of distal nephron segments forming functional homomeric (Kir4.1) and heteromeric (Kir4.1/Kir5.1) potassium channels that play an essential role in establishing a negative basolateral membrane potential and recycling K+ ions moved into the cytosol by the Na+/K+‐ATPase. In the present study we examined the effect of pharmacological inhibition of Kir4.1 and Kir4.1/Kir5.1 channels on sodium transport through the epithelial Na+ channel (ENaC) in the cortical collecting duct (CCD) cells. We have reported recently that Kir4.1 inhibitor nortriptyline (100 μM), but not fluoxetine (100 μM) inhibited whole‐cell potassium currents recorded from native principal CCD cells. First we examined whether fluoxetine and nortriptyline have different selectivity in targeting Kir4.1 and Kir4.1/Kir5.1 expressed in Chinese hamster ovary (CHO) cells. Single channel analysis revealed that application of 100 μM of amitriptyline produces a significant decrease in NPo of Kir4.1/Kir5.1 but does not affect Kir4.1 current activity, whereas fluoxetine selectively inhibits Kir4.1. Next we examined whether selective inhibition of Kir4.1 and Kir4.1/Kir5.1 affects an apical sodium transport via ENaC. We showed that amitriptyline, but not fluoxetine reduced (IC50=15.0 μM) the amiloride‐sensitive short‐circuit current (ISC) measured in polarized epithelial mCCDcl1 cells. In control experiments, application of amitriptyline did not directly affect ENaC activity overexpressed in CHO cells. Using different concentrations of recently developed Kir4.1 inhibitor, VU0134992, and patch‐clamp studies of single‐channel activity on mCCD cell line and native rodent and human CCD tubules, we confirmed that inhibition of Kir4.1/Kir5.1 channel but not Kir4.1 produces suppressive effect on ENaC activity. In summary, inhibition of Kir4.1/Kir5.1 channels in CCD cells indirectly reduces apical sodium conductance through ENaC, demonstrating the importance of basolateral potassium channels in the control of sodium reabsorption in distal nephron.Support or Funding InformationNational Institutes of Health grants R01 DK120821 (to J.D. and A.S.), R56 DK121750 (to O.P.), and R35 HL135749 (to A.S.)

Circadian regulation of cardiovascular and kidney function.

Video slideshow introduction to the symposium by symposium organiser David Pollock can be found here.

FoxO1 inhibits transcription and membrane trafficking of epithelial Na+ channel.

The epithelial Na(+) channel (ENaC), regulated by insulin, is of fundamental importance in the control of Na(+) reabsorption in the distal nephron. The potential role of Forkhead box O1 (FoxO1), downstream of insulin signaling, in the regulation of ENaC remains to be investigated. Here, we found that the overexpression of a constitutively active form of FoxO1 (ADA-FoxO1) suppressed the mRNA level of the ENaC α subunit (α-ENaC; also known as SCCN1A) and the apical density of ENaC in mouse cortical collecting duct (mCCD) cells. Conversely, knockdown of FoxO1 increased the apical membrane levels of α-ENaC and Na(+) transport under basal conditions. Insulin elevated α-ENaC expression and induced FoxO1 phosphorylation; however, the increase in α-ENaC and phosphorylated FoxO1 expression observed with insulin treatment was blunted ∼ 60% in cells expressing ADA-FoxO1. Moreover, insulin induced the interaction between phosphorylated FoxO1 and 14-3-3ε, indicating that FoxO1 phosphorylation promotes ENaC membrane trafficking by binding to 14-3-3ε. FoxO1 also suppressed activity of the α-ENaC promoter, and the putative FoxO1 target site is located in the -500 to -200 nt region of the α-ENaC promoter. These findings indicate that FoxO1 is a key negative regulatory factor in the insulin-dependent control of ENaC expression and forward trafficking in mCCD epithelia.

The Mineralocorticoid Receptor in Heart

See related article, pp 746–754 The mineralocorticoid receptor (MR) antagonists (MRAs) spironolactone and eplerenone have beneficial effects in patients with heart failure (HF) or left ventricular dysfunction.1 This underscores the major role of an inadequate hormonal stimulation leading to MR activation in HF. However, the actions of MRAs are complex and several questions remained unsolved. Which biochemical pathways are activated by the hormone that binds the cardiac MR? Which hormone binds the cardiac MR? In which pathological settings are the MRAs most appropriately used? The MR is the intracellular receptor of aldosterone. The hormone-receptor complex binds to a specific DNA sequence and triggers the transcription of target genes. In epithelial cells, the induced genes are mostly involved in the control of sodium reabsorption. However, the link between the beneficial effects of MRA in HF and these actions related to sodium control are unclear. Spironolactone is efficient in HF patients at a subhypotensive dose that likely did not involve diuretic effects. This suggests that spironolactone action in this setting was, at least in part, directed toward the MR of nonepithelial cells. Disappropriately increased levels of aldosterone in plasma are associated with inflammation and fibrosis in heart and blood vessels. Indeed, improved outcomes with spironolactone in HF have been linked to the antifibrotic effects of spironolactone. The MR is expressed in several cardiac cell types, cardiomyocytes and fibroblasts, and in vascular endothelial and smooth muscle cells, raising the question of its function in these tissues. Genetic technologies in mice have allowed selective deletion or overexpression of MR in different cardiac cell types. These tricky experimentations give novel and interesting informations. The study …

The Renal Epithelial Sodium Channel: Genetic Heterogeneity and Implications for the Treatment of High Blood Pressure

The renal epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium reabsorption through the distal nephron. ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium channel activity (Liddle's Syndrome and Pseudohypoaldosteronism type 1 associated with contrasting effects on blood pressure). Subtle dysregulation of ENaC however may also be important in essential hypertension - a common condition and a major cause of cardiovascular morbidity and mortality. The epithelial sodium channel is formed from three partly homologous subunits. In this review we deals firstly with current views of structural and functional features of the renal epithelial sodium channel with particular emphasis on mechanisms and processes involved in the control of sodium channel activity at the biochemical and cellular levels. We then focus on genetic aspects with reference to the significance of genetic variation in the sodium channel genes in relation to blood pressure. In particular, we review recent investigations on the potential clinical significance of mutations within the genes encoding ENaC subunits in individuals with high blood pressure. Lastly, we also examine the potential value of pharmacological targeting of the renal epithelial sodium channel with the sodium channel inhibitor amiloride for the treatment of hypertension.

Influence of the renal medullary circulation on the control of sodium excretion.

Although the role of the renal medullary circulation in the control of urinary concentrating ability is well established, its potential influence on tubular sodium reabsorption is not generally recognized. Nearly 30 years ago, changes in the intrarenal distribution of blood flow were first proposed to contribute to the natriuretic response to volume expansion. However, the lack of reliable methods for studying medullary blood flow limited progress in this area. The recent development of laser-Doppler flowmetry and videomicroscopic techniques for the study of the vasa recta circulation has renewed interest in the role of medullary hemodynamics in the control of sodium reabsorption. Results of these studies indicate that changes in renal medullary hemodynamics alter renal interstitial pressure and the medullary solute gradient and play an important role in the natriuretic response to elevations in renal perfusion pressure, intravenous infusion of saline, and changes in tubular sodium reabsorption produced by vasoactive compounds. What is emerging from these studies is the view that changes in renal medullary hemodynamics represent an important but misunderstood and long-ignored factor in the control of tubular sodium reabsorption.

Renal Disease,

As a subspecialty of internal medicine, nephrology seems blessed with more than its just share of outstanding teachers. An impressively large number of them appear together as contributors to the third edition of Professor Black's text on renal disease. Earlier editions of this work have been readable, informative, and enjoyable. Edition 3 carries on the precedent. Its text flows, despite its multiple authorship. Many readers will quickly feel that they sit with their teachers to learn the complexities of modern nephrology. Outstanding contributions are offered by de Wardener on the control of sodium reabsorption, Hodson on radiology of the kidney, Cameron on the natural history of glomerulonephritis, and Peart on hypertension. The discussion of diuretics by Lant and Wilson is comprehensive, interesting, and enhanced by attention to the molecular structures of the various agents. Misra presents an excellent review of what is known about glomerular basement membrane. His chapter

Renal Disease

One can easily imagine the instructions given by Dr. Black to his several authors. "Write a state of the art essay for me on the following topic. Do not be afraid to use humor and wit. Do not be reluctant to appear literate." Most of his contributors have complied with these instructions. What has emerged is a large volume, physically resembling a textbook, but in reality comprising an excellent series of brief essays. Some of the topics are relatively new to hardcover nephrological literature. For example, whole chapters on glomerular basement membrane and on therapeutic trials in renal disease are welcome newcomers. Portions of chapters dealing with pharmacodynamics, erythropoietin, and other topics are equally welcome. Robinson on "Principles of Renal Physiology," De Wardener on "Control of Sodium Reabsorption," and Kerr on "Acute Renal Failure" beautifully demonstrate the art of summarizing familiar material skillfully and gracefully. The editor himself appears in

Control of sodium reabsorption.

Control of sodium reabsorption.

Control of sodium reabsorption.

Control of sodium reabsorption.

Relation of pressure and flow to control of sodium reabsorption in the proximal tubule.

Relation of pressure and flow to control of sodium reabsorption in the proximal tubule.