Differential Regulation of Autophagy on Urine-Concentrating Capability through Modulating the Renal AQP2 Expression and Renin-Angiotensin System in Mice.

Abstract

Autophagy, a cellular process of "self-eating", plays an essential role in renal pathophysiology. However, the effect of autophagy on urine-concentrating ability in physiological conditions is still unknown. This study aimed to determine the relevance and mechanisms of autophagy for maintaining urine-concentrating capability during antidiuresis. The extent of the autophagic response to water deprivation (WD) was different between the renal cortex and medulla in mice. Autophagy activity levels in the renal cortex were initially suppressed and then stimulated by WD in a time‑dependent manner. During 48h WD, the urine-concentrating capability of mice was impaired by rapamycin but not 3-Methyladenine, accompanied by the suppressed renal aquaporin 2 (AQP2), V2 receptor (V2R), renin, and angiotensin-converting enzyme (ACE) expression, and the levels of prorenin/renin, angiotensin II (AngII), and aldosterone in the plasma and urine. In contrast, 3-Methyladenine and chloroquine suppressed the urine-concentrating capability in WD72 mice, accompanied by downregulation of AQP2 and V2R expression in the renal cortex. 3-Methyladenine and chloroquine further increased AQP2 and V2R expression in the renal medulla of WD72 mice. Compared to 3-MA and CQ, Rapa administration yielded completely opposite results on the above parameters in WD72 mice. In addition, 3-Methyladenine and chloroquine abolished the upregulation of prorenin/renin, AngII, and aldosterone levels in the plasma and urine in WD72mice. Taken together, our study demonstrated that autophagy regulated urine-concentrating capability through differential regulation of the renal AQP2/V2R and ACE/AngII signaling during WD.