Hormone-Dependent Regulation of Renin and Effects on Prorenin Receptor Signaling in the Collecting Duct

Abstract

The production of renin by the principal cells of the collecting duct has widened our understanding of the regulation of intrarenal angiotensin II (Ang II) generation and blood pressure. In the collecting duct, Ang II increases the synthesis and secretion of renin by mechanisms involving the activation of Ang II type 1 receptor (AT1R) via stimulation of the PKCα, Ca²⁺, and cAMP/PKA/CREB pathways. Additionally, paracrine mediators, including vasopressin (AVP), prostaglandins, bradykinin (BK), and atrial natriuretic peptide (ANP), regulate renin in principal cells. During Ang II-dependent hypertension, despite plasma renin activity suppression, renin and prorenin receptor (RPR) are upregulated in the collecting duct and promote de novo formation of intratubular Ang II. Furthermore, activation of PRR by its natural agonists, prorenin and renin, may contribute to the stimulation of profibrotic factors independent of Ang II. Thus, the interactions of RAS components with paracrine hormones within the collecting duct enable tubular compartmentalization of the RAS to orchestrate complex mechanisms that increase intrarenal Ang II, Na+ reabsorption, and blood pressure.

Keywords: bradykinin; intrarenal angiotensin II; nitric oxide; prostaglandins; protein kinase; vasopressin.

Figure 1.

The “Janus effect” mechanism. (A) Synthesis and release of JG renin: Transcription of Ren 1c gene gives rise to a pre-prorenin. Then, prorenin is formed by the removal of the (pro)segment and is sorted into two different pathways: a constitutive pathway for the secretion of the precursor prorenin and a regulated pathway for the secretion of mature renin. An example of Western blot detection for renin in collecting duct (CD) cells is provided. This sorting is determined by the glycosylation. Only glycosylated prorenin (46 kDa) can be directed to the vesicular network in the juxtaglomerular cells. The pro segment (a 43 aa segment) is proteolytically removed forming the active renin with approximately a 38 kDa molecular mass. Renin remains stored in vesicles awaiting controlled release. Non-glycosylated prorenin (41 kDa) is directed to a preeminent electron dense vesicular network that directly release prorenin that was initially believed to have no biological activity. Main regulatory regions in the Ren 1c gene that mediates activation or suppression of the transcription are mediated by CREB transcription factor, which is activated by cAMP/protein kinase A (PKA) pathway. Many receptors that induced PKA regulates positively renin gene expression such as β1 adrenergic and E-prostanoid 4 (EP4) receptors are mediated by CREB phosphorylation. The Ca²⁺/protein kinase C (PKC) pathway mediated by the Ang II AT1R suppresses renin exocytosis in a phenomenon called the Ca²⁺ paradox. The crosstalk between these pathways exerts a fine tune regulation on renin release by a Ca²⁺-dependent mechanism to lower intracellular cAMP levels. As a secondary modulation of renin in JG cells, cGMP generated by particulate guanylyl cyclase, activates protein kinase G type II (PKG-II) that inhibits renin secretion. (B) Synthesis and secretion of CD renin: Molecular mechanisms involved in CD renin regulation. Ang II/AT1R increases intracellular Ca²⁺ mobilization and PKC activity (red pathway). The AVP/V2 receptor agonist, DDAVP, increases renin synthesis and secretion via PKA/CREB, independently of the Ang II/AT1R (green pathway), indicating that in the CD, both Ca²⁺/PKC and PKA/CREB mediates the stimulation of CD renin. We proposed that these 2 pathways act synergistically to increase CD renin. BK- and ANP-dependent (yellow pathways) stimulation of renin gene expression in collecting duct cells involves the stimulation of nitric oxide (NO). BK/B2R also activates PKC-dependent renin release (yellow pathway). It remains unknown how NO and PKG act to increase CD renin (orange arrows). For more comprehensive diagrams of complete mechanisms of JG renin vs CD renin and their functional roles in the kidney, please consult to previous publications by our group [33, 96].