Angiotensin II acts through Rac1 to upregulate pendrin: Role of NADPH oxidase

This study explored the role of the small GTPase, Rac1, in pendrin's regulation by angiotensin II. To do this, we generated intercalated cell Rac1 knockout mice and observed that IC Rac1 gene ablation reduced pendrin's relative abundance in the apical region of intercalated cells in angiotensin II-treated, but not from vehicle-treated mice. Similarly, the Rac1 inhibitor, EHT 1864, reduced apical pendrin abundance in angiotensin II-treated mice, through a mechanism that does not require aldosterone. This IC angiotensin II-Rac1 signaling cascade modulates pendrin subcellular distribution without significantly changing actin organization. However, NADPH oxidase inhibition with APX 115 reduced apical pendrin abundance in vivo in ang II-treated mice. Moreover, superoxide dismutase mimetics reduced Cl- absorption in ang II-treated CCDs perfused in vitro. Since Rac1 is an NADPH subunit, Rac1 may modulate pendrin through NADPH oxidase-mediated reactive oxygen species (ROS) production. Because pendrin gene ablation blunts the pressor response to ang II, we asked if pendrin blunts the angiotensin II-induced increase in kidney superoxide. While kidney superoxide was similar in vehicle-treated wild type and pendrin KO mice, it was lower in angiotensin II-treated pendrin null than wild type kidneys. We conclude that angiotensin II acts through Rac1, independently of aldosterone, to increase apical pendrin abundance. Rac1 may stimulate pendrin, at least partly, through NADPH oxidase. This ...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Source Type: research