Bradykinin/B₂receptor activation regulates renin in M-1 cells via protein kinase C and nitric oxide

Abstract

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 B2 receptor (B2R) 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 B2R 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 B2R 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 B2R knockout and conditional B2R 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 B2R 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.

Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct

“…Although, cAMP/PKA is the main signaling pathway involved in CREB phosphorylation, PKC can also phosphorylate CREB ( Brindle and Montminy, 1992 ). However, we demonstrated that in the CD, the PKC pathway plays a major effect on the activation of renin synthesis ( Gonzalez et al, 2015 , 2017 ; Lara et al, 2017 ).…”

“…It is worth highlighting that L-NAME inhibits all three isoforms of NOS; thus L-NAME- induced responses cannot be interpreted as the involvement of eNOS only, as demonstrated in the CD-eNOS-KO mouse model. Accordingly, we previously showed that BK stimulates CD-renin synthesis and secretion via the B2R, and the subsequent PKC and NO pathways ( Lara et al, 2017 ). Independent of renin localization, either in JG or principal cells of the CD, its synthesis is mediated by phosphorylation of the transcriptional factor CRE-binding protein (CREB) ( Gomez et al, 2014 ; Gonzalez et al, 2015 ).…”

“…In mice, the augmented urinary excretion of the renin substrate, angiotensinogen (AGT), positively correlates with renal Ang II concentration and increases systolic blood pressure, but not plasma Ang II ( Kurtz and Wagner, 1998 ; Kobori et al, 2002 , 2003 ), supporting the concept that intratubular RAS activation contributes to the pathogenesis of hypertension. In contrast to JG-renin, Ang II acts in a feed-forward fashion to stimulate CD-renin synthesis and secretion via Ang II type 1 receptor (AT1R) through a Ca 2+ /PKCα-dependent augmentation of cAMP and activation of PKA/CREB pathway ( Gonzalez et al, 2011 ; Lara et al, 2017 ). Furthermore, the activation of the BK/B2 receptor (B2R) increases CD-renin synthesis and secretion through PKC stimulation and NO release in mouse CD cells ( Lara et al, 2017 ).…”

“…In contrast to JG-renin, Ang II acts in a feed-forward fashion to stimulate CD-renin synthesis and secretion via Ang II type 1 receptor (AT1R) through a Ca 2+ /PKCα-dependent augmentation of cAMP and activation of PKA/CREB pathway ( Gonzalez et al, 2011 ; Lara et al, 2017 ). Furthermore, the activation of the BK/B2 receptor (B2R) increases CD-renin synthesis and secretion through PKC stimulation and NO release in mouse CD cells ( Lara et al, 2017 ). In that study, we observed that L-NAME, an L-arginine analog that inhibits NO synthase (NOS) activity, completely blocked BK/B2R-stimulated CD-renin.…”

“…In that study, we observed that L-NAME, an L-arginine analog that inhibits NO synthase (NOS) activity, completely blocked BK/B2R-stimulated CD-renin. However, L-NAME, per se , increased CD-renin synthesis ( Lara et al, 2017 ). This observation suggests that in pathophysiological conditions associated with decreases in NO bioavailability, as occurs in hypertension ( Kobori et al, 2003 ), CD-renin is augmented and contributes to intrarenal RAS activation.…”