Hypotonicity-Induced Renin Exocytosis from Juxtaglomerular Cells Requires Aquaporin-1 and Cyclooxygenase-2

The mechanism by which extracellular hypotonicity stimulates release of renin from juxtaglomerular (JG) cells is unknown. We hypothesized that osmotically induced renin release depends on water movement through aquaporin-1 (AQP1) water channels and subsequent prostanoid formation. We recorded membrane capacitance (C-m) by whole-cell patch clamp in single JG cells as an index of exocytosis. Hypotonicity increased C-m significantly and enhanced outward current. Indomethacin, PLA(2) inhibition, and an antagonist of prostaglandin transport impaired the C-m and current responses to hypotonicity. Hypotonicity also increased exocytosis as determined by a decrease in single JIG cell quinacrine fluorescence in an indomethacin-sensitive manner. In single JIG cells from COX-2(-/-) and AQP1(-/-) mice, hypotonicity increased neither C-m nor outward current, but 0.1-mu M PGE(2) increased both in these cells. A reduction in osmolality enhanced cAMP accumulation in JIG cells but not in renin-producing As4.1 cells; only the former had detectable AQP1 expression. Inhibition of protein kinase A blocked the hypotonicity-induced C-m and current response in JG cells. Taken together, our results show that a 5 to 7% decrease in extracellular tonicity leads to AQP1-mediated water influx in JIG cells, PLA(2)/COX-2-mediated prostaglandin-dependent formation of cAMP, and activation of PKA, which promotes exocytosis of renin.