Bradykinin/B 2 receptor activation regulates renin in M‐1 cells via protein kinase C and nitric oxide

In the collecting duct ( CD ), the interactions of renin angiotensin system ( RAS ) and kallikrein‐kinin system ( KKS ) modulate Na + reabsorption, volume homeostasis, and blood pressure. In this study, we used a mouse kidney cortical CD cell line (M‐1 cells) to test the hypothesis that in the CD , the activation of bradykinin B 2 receptor (B 2 R) increases renin synthesis and release. Physiological concentrations of bradykinin ( BK ) treatment of M‐1 cells increased renin mRNA and prorenin and renin protein contents in a dose‐dependent manner and increased threefold renin content in the cell culture media. These effects were mediated by protein kinase C ( PKC ) independently of protein kinase A ( PKA ) because B 2 R antagonism with Icatibant and PKC inhibition with calphostin C, prevented these responses, but PKA inhibition with H89 did not modify the effects elicited by the B 2 R activation. BK ‐dependent stimulation of renin gene expression in CD cells also involved nitric oxide ( NO ) pathway because increased cGMP levels and inhibition of NO synthase with L‐ NAME prevented it. Complementary renin immunohistochemical studies performed in kidneys from mice with conventional B 2 R knockout and conditional B 2 R knockout in the CD , showed marked decreased renin immunoreactivity in CD , regardless of the renin presence in juxtaglomerular cells in the knockout mice. These results indicate that the activation of B 2 R increases renin synthesis and release by the CD cells through PKC stimulation and NO release, which support further the interactions between the RAS and KKS.