The mammalian distal convoluted tubule (DCT) makes an important contribution to potassium homeostasis by modulating NaCl transport. The thiazide-sensitive Na/Cl cotransporter (NCC) is activated by low potassium intake and by hypokalemia. Coupled with suppression of aldosterone secretion, activation of NCC helps to retain potassium by increasing electroneutral NaCl reabsorption, therefore reducing Na/K exchange. Yet the mechanisms by which DCT cells sense plasma potassium concentration and transmit the information to the apical membrane are not clear. Here, we tested the hypothesis that the potassium channel Kir4.1 is the potassium sensor of DCT cells. We generated mice in which Kir4.1 could be deleted in the kidney after the mice are fully developed. Deletion of Kir4.1 in these mice led to moderate salt wasting, low BP, and profound potassium wasting. Basolateral membranes of DCT cells were depolarized, nearly devoid of conductive potassium transport, and unresponsive to plasma potassium concentration. Although renal WNK4 abundance increased after Kir4.1 deletion, NCC abundance and function decreased, suggesting that membrane depolarization uncouples WNK kinases from NCC. Together, these results indicate that Kir4.1 mediates potassium sensing by DCT cells and couples this signal to apical transport processes.

Daily dietary potassium (K+) intake may be as large as the extracellular K+ pool. To avoid acute hyperkalemia, rapid removal of K+ from the extracellular space is essential. This is achieved by translocating K+ into cells and increasing urinary K+ excretion. Emerging data now indicate that the renal thiazide-sensitive NaCl cotransporter (NCC) is critically involved in this homeostatic kaliuretic response. This suggests that the early distal convoluted tubule (DCT) is a K+ sensor that can modify sodium (Na+) delivery to downstream segments to promote or limit K+ secretion. K+ sensing is mediated by the basolateral K+ channels Kir4.1/5.1, a capacity that the DCT likely shares with other nephron segments. Thus, next to K+-induced aldosterone secretion, K+ sensing by renal epithelial cells represents a second feedback mechanism to control K+ balance. NCC’s role in K+ homeostasis has both physiological and pathophysiological implications. During hypovolemia, NCC activation by the renin-angiotensin system stimulates Na+ reabsorption while preventing K+ secretion. Conversely, NCC inactivation by high dietary K+ intake maximizes kaliuresis and limits Na+ retention, despite high aldosterone levels. NCC activation by a low-K+ diet contributes to salt-sensitive hypertension. K+-induced natriuresis through NCC offers a novel explanation for the antihypertensive effects of a high-K+ diet. A possible role for K+ in chronic kidney disease is also emerging, as epidemiological data reveal associations between higher urinary K+ excretion and improved renal outcomes. This comprehensive review will embed these novel insights on NCC regulation into existing concepts of K+ homeostasis in health and disease.

Kir4.1 in the distal convoluted tubule plays a key role in sensing plasma potassium and in modulating the thiazide-sensitive sodium-chloride cotransporter (NCC). Here we tested whether dietary potassium intake modulates Kir4.1 and whether this is essential for mediating the effect of potassium diet on NCC. High potassium intake inhibited the basolateral 40 pS potassium channel (a Kir4.1/5.1 heterotetramer) in the distal convoluted tubule, decreased basolateral potassium conductance, and depolarized the distal convoluted tubule membrane in Kcnj10flox/flox mice, herein referred to as control mice. In contrast, low potassium intake activated Kir4.1, increased potassium currents, and hyperpolarized the distal convoluted tubule membrane. These effects of dietary potassium intake on the basolateral potassium conductance and membrane potential in the distal convoluted tubule were completely absent in inducible kidney-specific Kir4.1 knockout mice. Furthermore, high potassium intake decreased, whereas low potassium intake increased the abundance of NCC expression only in the control but not in kidney-specific Kir4.1 knockout mice. Renal clearance studies demonstrated that low potassium augmented, while high potassium diminished, hydrochlorothiazide-induced natriuresis in control mice. Disruption of Kir4.1 significantly increased basal urinary sodium excretion but it abolished the natriuretic effect of hydrochlorothiazide. Finally, hypokalemia and metabolic alkalosis in kidney-specific Kir4.1 knockout mice were exacerbated by potassium restriction and only partially corrected by a high-potassium diet. Thus, Kir4.1 plays an essential role in mediating the effect of dietary potassium intake on NCC activity and potassium homeostasis.

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Cuevas CA, Gonzalez AA, Inestrosa NC, Vio CP, Prieto MC. Angiotensin II increases fibronectin and collagen I through the ␤-catenin-dependent signaling in mouse collecting duct cells. Am J Physiol Renal Physiol 308: F358 -F365, 2015. First published November 19, 2014 doi:10.1152/ajprenal.00429.2014.-The contribution of angiotensin II (ANG II) to renal and tubular fibrosis has been widely reported. Recent studies have shown that collecting duct cells can undergo mesenchymal transition suggesting that collecting duct cells are involved in interstitial fibrosis. The Wnt/␤-catenin signaling pathway plays an essential role in development, organogenesis, and tissue homeostasis; however, the dysregulation of this pathway has been linked to fibrosis. In this study, we investigated whether AT1 receptor activation induces the expression of fibronectin and collagen I via the ␤-catenin pathway in mouse collecting duct cell line M-1. ANG II (10 Ϫ7 M) treatment in M-1 cells increased mRNA, protein levels of fibronectin and collagen I, the ␤-catenin target genes (cyclin D1 and c-myc), and the myofibroblast phenotype. These effects were prevented by candesartan, an AT 1 receptor blocker. Inhibition of the ␤-catenin degradation with pyrvinium pamoate (pyr; 10 Ϫ9 M) prevented the ANG II-induced expression of fibronectin, collagen I, and ␤-catenin target genes. ANG II treatment promoted the accumulation of ␤-catenin protein in a time-dependent manner. Because phosphorylation of glycogen synthase kinase-3␤ (GSK-3␤) inhibits ␤-catenin degradation, we further evaluated the effects of ANG II and ANG II plus pyr on p-ser9-GSK-3␤ levels. ANG II-dependent upregulation of ␤-catenin protein levels was correlated with GSK-3␤ phosphorylation. These effects were prevented by pyr. Our data indicate that in M-1 collecting duct cells, the ␤-catenin pathway mediates the stimulation of fibronectin and collagen I in response to AT 1 receptor activation. pyrvinium pamoate; mouse collecting duct cell; tissue homeostasis ANGIOTENSIN II (ANG II) plays a key role in the development and progression of chronic kidney disease (CKD) (27). It has been shown that increased levels of ANG II and renin in renal tubules after subtotal nephrectomy are pathogenically linked to the development of tubulointerstitial injury (10). In particular, alterations in the ANG type 1 (AT 1 ) receptor, angiotensin-converting enzyme 2 (ACE-2), and the newly described (pro)renin receptor precede the development of renal fibrosis (41). Evidence from in vivo studies has shown that AT 1 receptor antagonists ameliorate renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction (17). Furthermore, in vitro studies indicate that ANG II activates renal cells to produce profibrotic factors and extracellular matrix (ECM) proteins (37, 48, 51). These profibrotic factors lead to tubulointerstitial injury and glomerulosclerosis due to excessive accumulation and deposition of ECM components (3, 49), which are the final manifestations of CKD and renal failure (24). In the kidney...