Differential regulation of autophagy on urine-concentrating capability through modulating the renal AQP2 expression and renin-angiotensin system in mice.

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 48 h WD, the urine-concentrating capability of mice was impaired by rapamycin (Rapa) but not by 3-methyladenine (3-MA), accompanied by suppressed renal aquaporin 2 (AQP2), V₂ receptor (V₂R), renin, and angiotensin-converting enzyme (ACE) expression, and levels of prorenin/renin, angiotensin II (ANG II), and aldosterone in the plasma and urine. In contrast, 3-MA and chloroquine (CQ) suppressed the urine-concentrating capability in WD₇₂ mice, accompanied by downregulation of AQP2 and V₂R expression in the renal cortex. 3-MA and CQ further increased AQP2 and V₂R expression in the renal medulla of WD₇₂ mice. Compared with 3-MA and CQ, Rapa administration yielded completely opposite results on the above parameters in WD₇₂ mice. In addition, 3-MA and CQ abolished the upregulation of prorenin/renin, ANG II, and aldosterone levels in the plasma and urine in WD₇₂ mice. Taken together, our study demonstrated that autophagy regulated urine-concentrating capability through differential regulation of renal AQP2/V₂R and ACE/ANG II signaling during WD.NEW & NOTEWORTHY Autophagy exhibits a double-edged effect on cell survival and plays an essential role in renal pathophysiology. We for the first time reported a novel function of autophagy that controls the urine-concentrating capability in physiological conditions. We found that water deprivation (WD) differentially regulated autophagy in the kidneys of mice in a time-dependent manner and autophagy regulates the urine-concentrating capability mainly by regulating AQP2/V₂R and ACE/ANG II signaling in the renal cortex in WD mice.