Inhibitory effect of Ca2+ on renin secretion elicited by chemiosmotic stimuli through actomyosin mediation

We had previously shown that several experimental manipulations, which are likely to produce osmotic swelling of renin secretory granules, stimulate secretion of renin (C.S. Park, T.W. Honeyman, S. K. Ha, H. K. Choi, C. L. Chung, and C. D. Hong. J. Pharmacol. Exp. Ther. 259: 211-218, 1991). In subsequent studies, Ca2+ was found to block the stimulation of renin secretion evoked by osmotic swelling of renin secretion granules [Park, Hong, and Honeyman, Am. J. Physiol. 262 (Renal Fluid Electrolyte Physiol. 31): F793-F798, 1992]. Furthermore, evidence from our recent studies indicates that myosin light chain kinase (MLCK) might be involved in the inhibition of renin secretion through Ca(2+)-calmodulin. In the present study we investigate the possibility that MLCK might mediate the inhibitory action of Ca2+ on renin secretion stimulated by osmotic swelling of renin secretory granules. Rat renal cortical slices were incubated under a variety of experimental conditions that would produce osmotic swelling of renin secretory granules. Incubation in hypotonic KCl medium, isosmotic NH4Cl or CH3COONH4 medium, or isosmotic KCl or CH3COOK medium plus nigericin in the absence of Ca2+ all produced a significant increase in renin secretion 2- to 14-fold (P < 0.001). Ca2+ added to all of these media partially or completely blocked the stimulatory effects (P < 0.001). This inhibitory effect of Ca2+ was significantly blocked by ML-9 (10(-4) M, P < 0.001), a putative specific inhibitor of the Ca(2+)-calmodulin-dependent MLCK. Taken together, the present findings support the idea that the renin secretory response may involve chemiosmotic swelling of renin secretory granules. This pivotal step may be regulated by contractile actomyosin interaction, which is in turn modulated through the Ca(2+)-calmodulin-dependent activity of MLCK.