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 48h WD, the urine-concentrating capability of mice was impaired by rapamycin but not 3-Methyladenine, accompanied by the suppressed renal aquaporin 2 (AQP2), V receptor (VR), 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 WD mice, accompanied by downregulation of AQP2 and VR expression in the renal cortex. 3-Methyladenine and chloroquine further increased AQP2 and VR expression in the renal medulla of WD mice. Compared to 3-MA and CQ, Rapa administration yielded completely opposite results on the above parameters in WD mice. In addition, 3-Methyladenine and chloroquine abolished the upregulation of prorenin/renin, AngII, and aldosterone levels in the plasma and urine in WDmice. Taken together, our study demonstrated that autophagy regulated urine-concentrating capability through differential regulation of the renal AQP2/VR and ACE/AngII signaling during WD.