The epithelial Na ϩ channel, ENaC, and the Cl Ϫ /HCO 3 Ϫ exchanger, pendrin, mediate NaCl absorption within the cortical collecting duct and the connecting tubule. Although pendrin and ENaC localize to different cell types, ENaC subunit abundance and activity are lower in aldosterone-treated pendrin-null mice relative to wild-type mice. Because pendrin mediates HCO 3 Ϫ secretion, we asked if increasing distal delivery of HCO 3 Ϫ through a pendrin-independent mechanism "rescues" ENaC function in pen- 21: 192821: -194121: , 201021: . doi: 10.1681 Pendrin, encoded by Slc26a4, is an aldosterone-sensitive Cl Ϫ /HCO 3 Ϫ exchanger that mediates Cl Ϫ absorption and HCO 3 Ϫ secretion in the cortical collecting duct (CCD). 1-3 During NaCl restriction, pendrin-null mice excrete more NaCl than wild-type mice, which increases apparent vascular volume contraction and lowers BP. [3][4][5] The chloruresis observed in pendrin-null mice during NaCl restriction likely results from the absence of pendrin-mediated Cl Ϫ absorption. 3,4 However, because pendrin does not transport Na ϩ , the cause of the natriuresis observed in the mutant mice was explored further. After either dietary NaCl restriction or the administration of aldosterone, renal ENaC function and ENaC subunit abundance were lower in pendrin-null mice than in wildtype mice. 5 In particular, ␥ ENaC abundance was reduced in kidneys from pendrin-null mice relative to wild-type mice. However, how pendrin J Am Soc Nephrol

Pendrin is an anion exchanger expressed in the apical regions of B and non-A, non-B intercalated cells. Since angiotensin II increases pendrin-mediated Cl Ϫ absorption in vitro, we asked whether angiotensin II increases pendrin expression in vivo and whether angiotensin-induced hypertension is pendrin dependent. While blood pressure was similar in pendrin null and wild-type mice under basal conditions, following 2 wk of angiotensin II administration blood pressure was 31 mmHg lower in pendrin null than in wild-type mice. Thus pendrin null mice have a blunted pressor response to angiotensin II. Further experiments explored the effect of angiotensin on pendrin expression. Angiotensin II administration shifted pendrin label from the subapical space to the apical plasma membrane, independent of aldosterone. To explore the role of the angiotensin receptors in this response, pendrin abundance and subcellular distribution were examined in wild-type, angiotensin type 1a (Agtr1a) and type 2 receptor (Agtr2) null mice given 7 days of a NaCl-restricted diet (Ͻ 0.02% NaCl). Some mice received an Agtr1 inhibitor (candesartan) or vehicle. Both Agtr1a gene ablation and Agtr1 inhibitors shifted pendrin label from the apical plasma membrane to the subapical space, independent of the Agtr2 or nitric oxide (NO). However, Agtr1 ablation reduced pendrin protein abundance through the Agtr2 and NO. Thus angiotensin II-induced hypertension is pendrin dependent. Angiotensin II acts through the Agtr1a to shift pendrin from the subapical space to the apical plasma membrane. This Agtr1 action may be blunted by the Agtr2, which acts through NO to reduce pendrin protein abundance.angiotensin II type 1 receptor; chloride-bicarbonate exchanger; hypertension; connecting tubule; cortical collecting duct PENDRIN IS EXPRESSED IN THE apical regions of type B and non-A, non-B intercalated cells in the distal convoluted tubule (DCT), the connecting tubule (CNT), the initial collecting tubule (iCT), and the cortical collecting duct (CCD), where it mediates Cl Ϫ absorption and HCO 3 Ϫ secretion (17,30,35,36). Pendrin is upregulated when dietary NaCl is substituted with NaHCO 3 , although Na ϩ intake and circulating aldosterone concentration are the same in both models (29,31,34). Because renin, and probably angiotensin II, are increased when dietary Cl Ϫ is substituted for HCO 3 Ϫ (34), we asked whether pendrin is upregulated with angiotensin II administration in vivo through receptor-dependent signaling. The mouse kidney expresses multiple angiotensin II receptors (1a, 1b, and II) (9, 24), although most of the renal tubular effects of angiotensin II on NaCl transport are mediated by the type 1a receptor (Agtr1a) (3). In the absence of the Agtr1a (Agtr1a null mice), the pressor effect of angiotensin II is eliminated (13), in part, from the absence of the Agtr1-dependent renal NaCl absorption. While the renal localization of the Agtr1 is controversial (9, 15), functional studies have shown that angiotensin II applied in vitro regulates intercalated cell...