Evidence for two cellular pathways of renin secretion by the mouse submandibular gland

The pathway of renin secretion has been defined in the mouse submandibular gland (SMG). Renin is first synthesized as a prorenin, rapidly cleaved to a one-chain renin, and then very slowly processed to a two-chain form which is stored in mature granules. In pulse-labeling experiments of minced SMG, the swift appearance in the culture medium of radiolabeled one-chain renin, before granule formation, suggested that this form was secreted by a constitutive pathway independent of the granules, possibly directly from the Golgi. Supporting this hypothesis, phenylephrine, which stimulates the secretion of granules, causes a 4-fold increase in the two-chain renin, with little or no effect on the secretion of one-chain renin. Confirming evidence for the existence of the constitutive pathway was provided by the action of monensin, an ionophore that inhibits transport through the Golgi. Monensin inhibited the appearance of radiolabeled newly synthesized renin in the granules and medium while causing accumulation of the newly synthesized one-chain renin in the microsomes. Analysis of secreted renin by Western blot showed that monensin selectively inhibited the secretion of one-chain renin while not affecting the secretion of the stored two-chain renin. Taken together, our data suggest that one-chain renin is primarily secreted soon after synthesis by a pathway that bypasses the granules, while two-chain renin is secreted predominantly from the granules.