Angiotensin II Stimulates Renin in Inner Medullary Collecting Duct Cells via Protein Kinase C and Independent of Epithelial Sodium Channel and Mineralocorticoid Receptor Activity

Abstract

Abstract-Collecting duct (CD) renin is stimulated by angiotensin (Ang) II, providing a pathway for Ang I generation and further conversion to Ang II. Ang II stimulates the epithelial sodium channel via the Ang II type 1 receptor and increases mineralocorticoid receptor activity attributed to increased aldosterone release. Our objective was to determine whether CD renin augmentation is mediated directly by Ang II type 1 receptor or via the epithelial sodium channel and mineralocorticoid receptor. In vivo studies examined the effects of epithelial sodium channel blockade (amiloride; 5 mg/kg per day) on CD renin expression and urinary renin content in Ang II-infused rats (80 ng/min, 2 weeks). Ang II infusion increased systolic blood pressure, medullary renin mRNA, urinary renin content, and intrarenal Ang II levels. Amiloride cotreatment did not alter these responses despite a reduction in the rate of progression of systolic blood pressure. In primary cultures of inner medullary CD cells, renin mRNA and (pro)renin protein levels increased with Ang II (100 nmol/L), and candesartan (Ang II type 1 receptor antagonist) prevented this effect. Aldosterone (10 Ϫ10 to 10 Ϫ7 mol/L) with or without amiloride did not modify the upregulation of renin mRNA in Ang II-treated cells. However, inhibition of protein kinase C with calphostin C prevented the Ang II-mediated increases in renin mRNA and (pro)renin protein levels. Furthermore, protein kinase C activation with phorbol 12-myristate 13-acetate increased renin expression to the same extent as Ang II. These data indicate that an Ang II type 1 receptor-mediated increase in CD renin is induced directly by Ang II via the protein kinase C pathway and that this regulation is independent of mineralocorticoid receptor activation or epithelial sodium channel activity. Key Words: angiotensin II-dependent hypertension Ⅲ collecting duct renin Ⅲ renin gene expression Ⅲ protein kinase C Ⅲ cell signaling pathway R egulation of renin expression in the kidney juxtaglomerular (JG) apparatus has been widely studied; however, the mechanisms regulating expression of renin in collecting ducts (CDs) and its augmentation in animal models of hypertension remain unclear. 1,2 Increased renin synthesis is mediated by the angiotensin II (Ang II) type 1 receptor (AT 1 R) independent of changes in blood pressure. 3,4 In vitro studies also suggest that CD renin synthesis and secretion can be directly increased by Ang II 5 ; however, the mechanisms involved are poorly understood.Ang II is present at high levels in the kidneys of hypertensive animals, 6 and an important fraction of this Ang II is generated by de novo synthesis 7 as a consequence of augmented angiotensinogen expression in proximal tubule cells, leading to augmented angiotensinogen excretion in urine. 8,9 Along with the expression of angiotensin-converting enzyme in the distal nephron, 10 increases in CD renin expression and activity may have a key role in the intrarenal Ang II content, contributing to additional Ang II generation in distal ne...

Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

“…1A), consistent with previous reports (12,19,32). DDAVP elicited dose-related increases in renin mRNA (306 Ϯ 30 vs. 100 Ϯ 12%, P Ͻ 0.001), prorenin (165 Ϯ 23 vs. 100 Ϯ 10%, P Ͻ 0.05), and renin (200 Ϯ 13 vs. 100 Ϯ 15%, P Ͻ 0.05) in cell lysates (Fig.…”

“…4). We previously showed that freshly isolated rat inner medullary CD cells express mainly prorenin and that its protein levels are stimulated by ANG II (12). In the present study using M-1 cells treated with either DDAVP or ANG II, we showed increases in prorenin and renin to the same extent, but not in response to a combined treatment, which only caused further increases in prorenin.…”

“…However, the lack of a potentiation effect of thapsigargin on AVP-dependent cAMP accumulation indicates that the increases in intracellular Ca 2ϩ may not play a major role on the responses elicited by AVP (20). Previous studies demonstrated that CD renin is upregulated by PKC activation and that the ANG II-mediated upregulation of renin is suppressed by PKC inhibitors (12). Studies in rat inner medullary CD cells showed that PKC inhibitors decrease cAMP accumulation (29).…”

“…These findings further support the formation of intratubular ANG II from sequential coordinated actions of tubular renin and ACE that act on AGT substrate delivered from the proximal segments. As evidence, ANG II, AGT, and renin contents are increased in the kidneys from ANG II-infused hypertensive rats (12), which contribute to sodium reabsorption (48). However, the mechanisms regulating renin in the CD and its physiological implications are not well understood.…”

Renin-angiotensin system in the kidney: What is new?

“…Local RAS was first described within the kidney over 20 years ago [29][30][31][32] , where the levels of Ang Ⅱ are much higher than in plasma [32,72] . Intrarenal Ang Ⅱ levels and local formation in the kidney have been reported by Navar and colleagues [11,32,[73][74][75][76] . In addition to Ang Ⅱ synthesis in the kidney, there are other well-described mechanisms that play a critical role in high renal Ang Ⅱ levels, and these occur after Ang II endocytosis with the AT1 receptor [77,78] .…”