Ren1c Homozygous Null Mice Are Hypotensive and Polyuric, but Heterozygotes Are Indistinguishable from Wild-Type

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525, USA.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 02/2005; 16(1):125-32. DOI: 10.1681/ASN.2004060490
Source: PubMed


Mice lacking Ren1c were generated using C57BL/6-derived embryonic stem cells. Mice homozygous for Ren1c disruption (Ren1c-/-) are born at the expected ratio, but approximately 80% die of dehydration within a few days. The surviving Ren1c-/- mice have no renin mRNA expression in the kidney, hydronephrosis, thickening of renal arterial walls, and fibrosis in the kidney. Plasma renin and angiotensins I and II are undetectable. Urinary aldosterone is 6% wild-type. They have low tail-cuff BP (84 +/- 4 versus 116 +/- 5 mmHg in +/+) and excrete large amounts of urine (5.2 +/- 0.8 ml/d, 725 +/- 34 mOsm versus 1.1 +/- 0.1 ml/d, 2460 +/- 170 mOsm in +/+). After 5 d of drinking 5% dextrose, desmopressin does not increase the osmolality of the urine in -/- mice (624 +/- 19 to 656 +/- 25 mOsm), whereas in +/+, it increases severalfold (583 +/- 44 to 2630 +/- 174 mOsm). Minipump infusion of angiotensin II to Ren1c-/- mice restores BP to wild-type level, but preexisting damage to the medulla prevents complete restoration of the ability of the kidney to concentrate urine. Heterozygous Ren1c+/- mice, in contrast, are indistinguishable from +/+ in BP, urine volume, and osmolality. Kidney renin mRNA, the number of kidney cells producing renin, and plasma renin concentration in the Ren1c+/- mice are also indistinguishable from +/+. These results demonstrate that renin is the only enzyme capable of maintaining plasma angiotensins and that renin expression in the kidney is very tightly regulated at the mRNA level.

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Available from: R. Ariel Gomez, Oct 06, 2015
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    • "AGT-, renin-, ACE-, or AT 1R-deficient mice exhibit virtually identical phenotypes characterized by vascular hyperplasia, hydronephrosis, hypoplastic medulla, and papilla [61–66]. Functionally, Renin-, ACE-, and AT 1R-null animals are polyuric and have a reduced ability to concentrate urine [63–65]. Deletion of the AT 2R in mice causes ectopic UB budding from the nephric duct, duplicated collecting systems, and hydronephrosis [67]. "
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    ABSTRACT: The renin-angiotensin system (RAS), a key regulator of the blood pressure and fluid/electrolyte homeostasis, also plays a critical role in kidney development. All the components of the RAS are expressed in the developing metanephros. Moreover, mutations in the genes encoding components of the RAS in mice or humans are associated with a broad spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). These forms of CAKUT include renal papillary hypoplasia, hydronephrosis, duplicated collecting system, renal tubular dysgenesis, renal vascular abnormalities, and aberrant glomerulogenesis. Emerging evidence indicates that (pro)renin receptor (PRR), a novel component of the RAS, is essential for proper kidney development and that aberrant PRR signaling is causally linked to cardiovascular and renal disease. This paper describes the role of the RAS in kidney development and highlights emerging insights into the cellular and molecular mechanisms by which the PRR may regulate this critical morphogenetic process.
    06/2011; 2011(2090-214X):247048. DOI:10.4061/2011/247048
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    • "The tail-cuff BP of the Ace−/− mice is ~73 mmHg, over 30 mmHg less than what is seen in wild-type mice [61]. This observation is similar to the phenotype of the Agt−/− mice [22] [23] [24], Ren1c−/− mice [27], and the Agtr1a−/ −; Agtr1b−/− double-null mice [62] [63], suggesting that the reduction of BP observed in Ace-knockout mice is due to the lack of Ang II production. "
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    ABSTRACT: The renin angiotensin system (RAS) is important for fluid and blood pressure regulation. Recent studies suggest that an overactive RAS is involved in the metabolic syndrome. This article discusses recent advances on how genetic alteration of the RAS affects cardiovascular and metabolic phenotypes, with a special emphasis on the potential role of angiotensin-independent effects of renin.
    The Open Hypertension Journal 01/2010; 3:1-13. DOI:10.2174/1876526203010001
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    • "Mutations in the genes encoding components of the renin-angiotensin system (RAS) or pharmacological inhibition of RAS in animals or humans cause diverse forms of CAKUT that include papillary and medullary hypodysplasia, hydronephrosis, collapsed collecting ducts, aberrant UB budding, duplicated collecting system, and urinary concentrating defect (Nagata et al., 1996; Niimura et al, 1995; Takahashi et al., 2005; Esther et al., 1996; Oliverio et al., 1998; Tsuchida et al., 1998). Since CAKUT are the major cause of renal failure in childhood (NAPRTCS Annual Report, 2006), identification of the molecular mechanisms that lead to diverse forms of CAKUT under conditions of disrupted RAS is critical. "
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    ABSTRACT: The renin-angiotensin system (RAS) plays a critical role in ureteric bud (UB) and kidney morphogenesis. Mutations in the genes encoding components of the RAS cause a spectrum of congenital abnormalities of the kidney and urinary tract (CAKUT). However, the mechanisms by which aberrations in the RAS result in CAKUT are poorly understood. Given that c-Ret receptor tyrosine kinase (RTK) is a major inducer of UB branching, the present study tested the hypothesis that angiotensin (Ang) II-induced activation of c-Ret plays a critical role in UB branching morphogenesis. E12.5 mice metanephroi were grown for 24h in the presence or absence of Ang II, Ang II AT(1) receptor (AT(1)R) antagonist candesartan, phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or ERK1/2 inhibitor PD98059. Ang II increased the number of UB tips (61+/-2.4 vs. 45+/-4.3, p<0.05) compared with control. Quantitative RT-PCR analysis demonstrated that Ang II increased c-Ret mRNA levels in the kidney (1.35+/-0.05 vs. 1.0+/-0, p<0.01) and in the UB cells (1.28+/-0.04 vs. 1.0+/-0, p<0.01) compared to control. This was accompanied by increased Tyr(1062)Ret phosphorylation by Ang II (5.5+/-0.9 vs. 1.8+/-0.4 relative units, p<0.05). In addition, treatment of UB cells with Ang II (10(-5)M) increased phosphorylation of Akt compared to control (213+/-16 vs. 100+/-20%, p<0.05). In contrast, treatment of metanephroi or UB cells with candesartan decreased c-Ret mRNA levels (0.72+/-0.06 vs. 1.0+/-0, p<0.01; 0.68+/-0.07 vs. 1.0+/-0, p<0.05, respectively) compared with control. Ang II-induced UB branching was abrogated by LY294002 (24+/-2.6 vs. 37+/-3.0, p<0.05) or PD98059 (33+/-2.0 vs. 48+/-2.2, p<0.01). These data demonstrate that Ang II-induced UB branching depends on activation of Akt and ERK1/2. We conclude that cross-talk between the RAS and c-Ret signaling plays an important role in the development of the renal collecting system.
    Mechanisms of development 12/2009; 127(1-2):21-7. DOI:10.1016/j.mod.2009.11.004 · 2.44 Impact Factor
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