Kidney Specific Regulation of Blood Pressure through Nedd4‐2

Abstract

Nedd4‐2 has been proposed to play a critical role in regulating epithelial Na+ channel (ENaC) activity through ubiquitination mediated degradation, and blood pressure (BP) regulation. To further understand the in vivo role of Nedd4‐2, we generated mice with global and kidney collecting duct (CD)‐specific inactivation of Nedd4‐2. The global knockout mice had higher BP on a normal diet, and a further increase in BP when on a high‐salt (HS) diet. The hypertension was mediated through ENaC, as both expression level and activity were increased in Nedd4‐2 null mice, and hypertension was substantially reduced in the presence of amiloride. However, unlike mice with global inactivation of Nedd4‐2, mice with CD‐specific inactivation did not have spontaneously elevated BP. When the mice were placed on HS diet, mice with CD‐specific inactivation of Nedd4‐2 had increased BP, although it was significantly lower than that of mice with global inactivation of Nedd4‐2. Overall, our results demonstrate that in vivo Nedd4‐2 is critical regulator of ENaC activity and BP, and suggest that kidney (CD) expression of Nedd4‐2 is necessary but not sufficient for the general increase in BP. Supported by NIH DK52617 to BY and JBS.