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

Takahashi, Nobuyuki; López, María Luisa S. Sequeira; Cowhig, John E.; Taylor, Melissa A.; Hatada, Tomoko; Riggs, Emily; Lee, Gene; Gómez, R. Ariel; Kim, Hyung Suk; Smithies, Oliver

doi:10.1681/asn.2004060490

Cited by 132 publications

(149 citation statements)

References 31 publications

(30 reference statements)

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“…Indeed, embryonic ablation of several RAS components in rodents results in renal developmental pathologies indicating the requirement of the RAS during renal development (23,55,66,71). Axitinib, a highly selective inhibitor of VEGF receptors 1-3, inhibits angiogenesis in both mammals (26) and zebrafish (8,81).…”

Section: Angiogenesis and Renin-expressing Cellsmentioning

confidence: 99%

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Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium

Rider

Mullins

Verdon

et al. 2015

American Journal of Physiology-Renal Physiology

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Rider SA, Mullins LJ, Verdon RF, MacRae CA, Mullins JJ. Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium. Am J Physiol Renal Physiol 309: F531-F539, 2015. First published July 22, 2015 doi:10.1152/ajprenal.00247.2015.-Although renin is a critical regulatory enzyme of the cardiovascular system, its roles in organogenesis and the establishment of cardiovascular homeostasis remain unclear. Mammalian renin-expressing cells are widespread in embryonic kidneys but are highly restricted, specialized endocrine cells in adults. With a functional pronephros, embryonic zebrafish are ideal for delineating the developmental functions of renin-expressing cells and the mechanisms governing renin transcription. Larval zebrafish renin expression originates in the mural cells of the juxtaglomerular anterior mesenteric artery and subsequently at extrarenal sites. The role of renin was determined by assessing responses to renin-angiotensin system blockade, salinity variation, and renal perfusion ablation. Renin expression did not respond to renal flow ablation but was modulated by inhibition of angiotensin-converting enzyme and altered salinity. Our data in larval fish are consistent with conservation of renin's physiological functions. Using transgenic renin reporter fish, with mindbomb and cloche mutants, we show that Notch signaling and the endothelium are essential for developmental renin expression. After inhibition of angiogenesis, renin-expressing cells precede angiogenic sprouts. Arising from separate lineages, but relying on mutual interplay with endothelial cells, renin-expressing cells are among the earliest mural cells observed in larval fish, performing both endocrine and paracrine functions. renin; zebrafish; notch; endothelium; angiogenesis RENIN is the rate-limiting enzyme of the renin-angiotensin system (RAS). Mammalian ANG II, the effector of the RAS, is principally involved in blood pressure homeostasis by regulation of vasomotor tone and Na ϩ retention. ANG II also regulates cell proliferation and angiogenesis (12,22). Pathological activation of the RAS is associated with cardiovascular diseases, including hypertension and heart failure, and is consequently a major target of therapeutic agents (11).Renin and its cognate cells are required for normal renal development (2), including angiogenesis of the renal vascular tree (59). In mice, ablation of the renin gene or renin-expressing cells leads to renal developmental abnormalities (55,71,79). The vasculature of mammalian embryonic kidneys have a transient but extensive coverage of mural renin-expressing cells (17,31,32,47,63); however, their function is unclear. Adult renin-expressing cells are restricted to the juxtaglomerular apparatus and play a vital role in ion homeostasis by secreting activated renin enzyme via cytoplasmic granules (17,31,36,63). Upon physiological challenge by RAS inhibition or low Na ϩ , prearteriolar vascular smooth muscle cells (VSMC) reestablish their embryonic re...

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Section: Angiogenesis and Renin-expressing Cellsmentioning

confidence: 99%

“…In mice, ablation of the renin gene or renin-expressing cells leads to renal developmental abnormalities (55,71,79). The vasculature of mammalian embryonic kidneys have a transient but extensive coverage of mural renin-expressing cells (17,31,32,47,63); however, their function is unclear.…”

mentioning

confidence: 99%

Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium

Rider

Mullins

Verdon

et al. 2015

American Journal of Physiology-Renal Physiology

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“…Af17 Ϫ/Ϫ mice share the low BP phenotype on a normal Na ϩ diet with Ren1c Ϫ/Ϫ , 36 AS Ϫ/Ϫ , 13 Agt Ϫ/Ϫ , 14 Ace Ϫ/Ϫ , 15 and WNK1 Ϯ 18 mice. Ren1c, AS, Agt, and Ace are key components of the renin-angiotensin-aldo system and thus are upstream regulators of ENaC.…”

Section: High Dietary Potassium Attenuated the Effect Of Af17mentioning

confidence: 99%

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Chen¹,

H²,

Pochynyuk

et al. 2011

Journal of the American Society of Nephrology

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The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP.

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“…Genetic defects [1][2][3] or pharmacological inhibition 4,5 of the renin-angiotensin system (RAS) during kidney development cause a massive compensatory increase in the number of renin-expressing cells associated with the development of multilayered preglomerular vessel walls. Indirect evidence suggests that a low kidney perfusion pressure associated with the aforementioned conditions could play a key role for the development of renin cell hyperplasia.…”

mentioning

confidence: 99%

Deletion of von Hippel–Lindau Protein Converts Renin-Producing Cells into Erythropoietin-Producing Cells

Kurt

Paliege

Willam

et al. 2013

Journal of the American Society of Nephrology

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States of low perfusion pressure of the kidney associate with hyperplasia or expansion of renin-producing cells, but it is unknown whether hypoxia-triggered genes contribute to these changes. Here, we stabilized hypoxia-inducible transcription factors (HIFs) in mice by conditionally deleting their negative regulator, Vhl, using the Cre/loxP system with renin-1d promoter-driven Cre expression. Vhl 2/2REN mice were viable and had normal BP. Deletion of Vhl resulted in constitutive accumulation of HIF-2a in afferent arterioles and glomerular cells and HIF-1a in collecting duct cells of the adult kidney. The preglomerular vascular tree developed normally, but far fewer renin-expressing cells were present, with more than 70% of glomeruli not containing renin cells at the typical juxtaglomerular position. Moreover, these mice had an attenuated expansion of renin-producing cells in response to a low-salt diet combined with an ACE inhibitor. However, renin-producing cells of Vhl 2/2REN mice expressed the erythropoietin gene, and they were markedly polycythemic. Taken together, these results suggest that hypoxia-inducible genes, regulated by VHL, are essential for normal development and physiologic adaptation of renin-producing cells. In addition, deletion of Vhl shifts the phenotype of juxtaglomerular cells from a renin-to erythropoietin-secreting cell type, presumably in response to HIF-2 accumulation.

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

Abstract: 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

Cited by 132 publications

References 31 publications

Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium

Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Deletion of von Hippel–Lindau Protein Converts Renin-Producing Cells into Erythropoietin-Producing Cells

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