Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice

Abstract

Pendrin (encoded by Pds, Slc26a4) is a Cl−/HCO3− exchanger expressed in the apical regions of type B and non-A, non-B intercalated cells of kidney and mediates renal Cl− absorption, particularly when upregulated. Aldosterone increases blood pressure by increasing absorption of both Na+ and Cl− through increased protein abundance and function of Na+ transporters, such as the epithelial Na+ channel (ENaC) and the Na+-Cl− cotransporter (NCC), as well as Cl− transporters, such as pendrin. Because aldosterone analogs do not increase blood pressure in Slc26a4−/− mice, we asked whether Na+ excretion and Na+ transporter protein abundance are altered in kidneys from these mutant mice. Thus wild-type and Slc26a4-null mice were given a NaCl-replete, a NaCl-restricted, or NaCl-replete diet and aldosterone or aldosterone analogs. Abundance of the major renal Na+ transporters was examined with immunoblots and immunohistochemistry. Slc26a4-null mice showed an impaired ability to conserve Na+ during dietary NaCl restriction. Under treatment conditions in which circulating aldosterone is increased, α-, β-, and 85-kDa γ-ENaC subunit protein abundances were reduced 15–35%, whereas abundance of the 70-kDa fragment of γ-ENaC was reduced ∼70% in Slc26a4-null relative to wild-type mice. Moreover, ENaC-dependent changes in transepithelial voltage were much lower in cortical collecting ducts from Slc26a4-null than from wild-type mice. Thus, in kidney, ENaC protein abundance and function are modulated by pendrin or through a pendrin-dependent downstream event. The reduced ENaC protein abundance and function observed in Slc26a4-null mice contribute to their lower blood pressure and reduced ability to conserve Na+ during NaCl restriction.

Collecting Duct Intercalated Cell Function and Regulation

“…Together these two transport proteins mediate the until recently unexplained thiazide-sensitive electroneutral NaCl reabsorption in the collecting duct (4,11,107). Moreover, pendrin deletion in type B intercalated cells disturbs the function of ENaC in adjacent principal cells (98,100). As in intercalated cells, NaCl absorption is energized by the H 1 -ATPase and not by the Na 1 /K 1 -ATPase (11); Eladari and colleagues hypothesized that Na 1 transport in type B intercalated cells was mediated by a bicarbonatedependent transport protein at the basolateral membrane.…”

“…Aldosterone and angiotensin II also increase the levels of pendrin (96,97), thus linking this transport protein to the maintenance of adequate extracellular volume and potentially to the development of hypertension. Recently, it has been proposed that pendrin may be activated via a kidney-specific mechanism that does not include circulating aldosterone (98). Furthermore, angiotensin II mediated pendrin upregulation and subcellular localization changes in kidney occur via the angiotensin 1a receptor (99).…”

“…Furthermore, angiotensin II mediated pendrin upregulation and subcellular localization changes in kidney occur via the angiotensin 1a receptor (99). Pendrinmediated Cl 2 uptake leads to vascular volume expansion and pendrin-induced modification of ENaC abundance and function (98). Changes in luminal bicarbonate concentration and/or pH could also contribute to this signaling (100).…”

Pendrin Modulates ENaC Function by Changing Luminal HCO3 −

“…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…”

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

“…Recent advances have identified an electroneutral transport pathway for chloride using the Cl − /bicarbonate exchanger (Slc26a4; pendrin) (6) and the Na + -driven Cl − /bicarbonate exchanger (Slc4a8; NDCBE) (7) in the β-intercalated cells (ICs) of CNT and CD. However, such an electroneutral pathway is not able to couple Cl − reabsorption with epithelial sodium channel (ENaC)-based Na + reabsorption that takes place in the principal cells (PCs) of CNT and CD (8), despite many efforts to connect ENaC and pendrin gene expression through endocrine or paracrine mechanisms (9,10). We and others have previously demonstrated the presence of a paracellular Cl − pathway or "chloride shunt" in vitro in the CNT and CD cells (11,12).…”