期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 22, 期 9, 页码 1707-1719出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2011020132
关键词
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资金
- Leducq Foundation Transatlantic Network on Hypertension
- National Institutes of Health [DK-64635, K08 DK081728]
- El Consejo Nacional de Ciencia y Tecnologia Mexico [59992]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK085097, K08 DK070668]
- Swiss National Science Foundation [31003A_125422/1]
- NCCR-Kidney.ch (Swiss National Science Foundation)
- Swiss Kidney Foundation
- Universidad Nacional Autonoma de Mexico
- Swiss National Science Foundation (SNF) [31003A_125422] Funding Source: Swiss National Science Foundation (SNF)
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+-C1(-) 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.
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