Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension

Abstract

The physiological and pathophysiological significance of collecting duct (CD)-derived renin, particularly as it relates to blood pressure (BP) regulation, is unknown. To address this question, we generated CD-specific renin knockout (KO) mice and examined BP and renal salt and water excretion. Mice containing loxP-flanked exon 1 of the renin gene were crossed with mice transgenic for aquaporin-2-Cre recombinase to achieve CD-specific renin KO. Compared with controls, CD renin KO mice had 70% lower medullary renin mRNA and 90% lower renin mRNA in microdissected cortical CD. Urinary renin levels were significantly lower in KO mice (45% of control levels) while plasma renin concentration was significantly higher in KO mice (63% higher than controls) during normal-Na intake. While no observable differences were noted in BP between the two groups with varying Na intake, infusion of angiotensin II at 400 ng·kg(-1)·min(-1) resulted in an attenuated hypertensive response in the KO mice (mean arterial pressure 111 ± 4 mmHg in KO vs. 128 ± 3 mmHg in controls). Urinary renin excretion and epithelial Na(+) channel (ENaC) remained significantly lower in the KO mice following ANG II infusion compared with controls. Furthermore, membrane-associated ENaC protein levels were significantly lower in KO mice following ANG II infusion. These findings suggest that CD renin modulates BP in ANG II-infused hypertension and these effects are associated with changes in ENaC expression.

Vascular versus tubular renin: role in kidney development

“…A recent study showed that deletion of renin in the collecting duct principal cells (using an aquaporin 2-Cre mouse) did not affect blood pressure, even varying Na intake (16). However, those mice had an attenuated response to ANG II-induced hypertension (16).…”

“…A recent study showed that deletion of renin in the collecting duct principal cells (using an aquaporin 2-Cre mouse) did not affect blood pressure, even varying Na intake (16). However, those mice had an attenuated response to ANG II-induced hypertension (16). Whether renin expression in the collecting duct plays a role during pathological processes still remains to be investigated, but in our study, deletion of renin in the tubular compartment did not result in any discernible morphological or physiological changes.…”

“…A recent study showed that ANG II-induced hypertension is attenuated in a principal cell-specific conditional knockout for renin, using a mouse expressing Cre-recombinase under the control of the Aquaporin 2 promoter (16). Whereas the contribution of RAS genes in ureteric bud branching and renal medulla development has been implied in a number of studies (11, 24 -26, 33), the contribution of tubular renin in overall kidney morphogenesis and development of the renal vasculature has not been established.…”

Sustained Activation of Wnt/β-Catenin Signaling Drives AKI to CKD Progression

“…Notably, weak renin staining was only observed in the juxtaglomerular apparatus of normal kidneys ( Figure 5F, open arrow), whereas renin was predominantly induced in renal tubular epithelial cells after kidney injury ( Figure 5F, solid arrows), consistent with previous observations. [31][32][33] We further investigated the effects of exogenous Wnt1 on matrix gene expression and renal fibrotic lesions after AKI. As shown in Figure 6, A-D, in vivo expression of exogenous Wnt1 significantly induced the mRNA expression of a-smooth muscle actin (a-SMA), fibronectin, and types I and III collagens in the kidneys after IRI as shown by qRT-PCR analyses.…”

Renin, Genes, MicroRNAs, and Renal Mechanisms Involved in Hypertension

“…[10][11][12][13] The involvement of an intrarenal renin-angiotensin system now seems to be an important component of the pathophysiological mechanisms involved in essential hypertension. [12][13][14][15][16][17][18][19] In the present review, I will first provide a brief summary of my earlier contributions to the hypertension field, these having been addressed in more detail in a review arising from my Lewis K. Dahl Memorial Lecture in 2010. 20 I will then review my more recent research, which has involved the determination of alterations in gene expression at the transcriptome-wide level in hypertension and the pivotal mechanistic insights this work has provided, especially an intriguing mechanism controlling intrarenal renin.…”