Abstract
Regulation of renal Na(+) transport is essential for controlling blood pressure, as well as Na(+) and K(+) homeostasis. Aldosterone stimulates Na(+) reabsorption by the Na(+)-Cl(-) cotransporter (NCC) in the distal convoluted tubule (DCT) and by the epithelial Na(+) channel (ENaC) in the late DCT, connecting tubule, and collecting duct. Aldosterone increases ENaC expression by inhibiting the channel's ubiquitylation and degradation; aldosterone promotes serum-glucocorticoid-regulated kinase SGK1-mediated phosphorylation of the ubiquitin-protein ligase Nedd4-2 on serine 328, which prevents the Nedd4-2/ENaC interaction. It is important to note that aldosterone increases NCC protein expression by an unknown post-translational mechanism. Here, we present evidence that Nedd4-2 coimmunoprecipitated with NCC and stimulated NCC ubiquitylation at the surface of transfected HEK293 cells. In Xenopus laevis oocytes, coexpression of NCC with wild-type Nedd4-2, but not its catalytically inactive mutant, strongly decreased NCC activity and surface expression. SGK1 prevented this inhibition in a kinase-dependent manner. Furthermore, deficiency of Nedd4-2 in the renal tubules of mice and in cultured mDCT(15) cells upregulated NCC. In contrast to ENaC, Nedd4-2-mediated inhibition of NCC did not require the PY-like motif of NCC. Moreover, the mutation of Nedd4-2 at either serine 328 or 222 did not affect SGK1 action, and mutation at both sites enhanced Nedd4-2 activity and abolished SGK1-dependent inhibition. Taken together, these results suggest that aldosterone modulates NCC protein expression via a pathway involving SGK1 and Nedd4-2 and provides an explanation for the well-known aldosterone-induced increase in NCC protein expression.
Highlights
The mineralocorticoid hormone aldosterone plays an important role in controlling Naϩ and Kϩ balance by enhancing Naϩ reabsorption or Kϩ secretion in the kidney
Aldosterone acts on the so-called aldosterone-sensitive distal nephron (ASDN), which is defined by the coexpression of the amiloride-sensitive epithelial Naϩ channel (ENaC), the mineralocorticoid receptor, the 11-hydroxysteroid dehydrogenase type 2, which prevents illicit occupation of mineralocorticoid receptor by glucocorticoids, and the serum/glucocorticoid-regulated kinase 1 (SGK1), which is a primary transducer of the aldosterone message.[1,2,3,4,5]
We propose that activation of the SGK1-Nedd[] pathway is an important mechanism for regulation of NCC activity during high aldosterone states
Summary
The mineralocorticoid hormone aldosterone plays an important role in controlling Naϩ and Kϩ balance by enhancing Naϩ reabsorption or Kϩ secretion in the kidney. It has been shown that aldosterone increases NCC expression by a post-translational mechanism, because the increased NCC protein levels, which are seen in experimental models of hyperaldosteronism, are not preceded or accompanied by an increase in NCC mRNA levels.[19,20,21,22] It is known that aldosterone’s effects in the ASDN are transduced by activation of the SGK1 kinase, which is only expressed in this part of the kidney.[23,24,25] Recently, it has been suggested that SGK1 could increase NCC activity by phosphorylating WNK4 and preventing the WNK4-induced inhibition of the cotransporter.[26]. The coexpression of 11-hydroxysteroid dehydrogenase type 2, SGK1, Nedd[], and NCC in DCT2 suggests that the post-translational increase of NCC induced by aldosterone could be explained through a mechanism involving SGK1 and Nedd[]. We propose that activation of the SGK1-Nedd[] pathway is an important mechanism for regulation of NCC activity during high aldosterone states
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