Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis

Gribouval, Olivier; Gonzalès, Marie; Neuhaus, Thomas J.; Aziza, Jacqueline; Bieth, Éric; Laurent, Nicole; Bouton, Jean Marie; Feuillet, François; Makni, S.; Amar, H. Ben; Laube, Guido F.; Delezoide, Anne‐Lise; Bouvier, Raymonde; Dijoud, Frédérique; Ollagnon‐Roman, Elisabeth; Roume, J.; Joubert, Madeleine; Antignac, Corinne; Gubler, Marie–Claire

doi:10.1038/ng1623

Cited by 256 publications

(227 citation statements)

References 23 publications

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“…The cardiovascular and developmental defects can be complemented in mice by substitution of the mouse RAS with their human orthologs (5) or by targeted expression of Ang-II (6). In humans, genetic defects in the RAS were reported to cause renal tubular dysgenesis, hypotension, and early stillbirth (7). Consequently, both the mouse and human genetic data illustrate the importance of the system both developmentally and in adults.…”

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confidence: 99%

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

Zhoux

Davis

2006

Journal of Biological Chemistry

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Renin is the rate-limiting enzyme in the renin-angiotensin system and thus dictates the level of the pressor hormone angiotensin-II. The classical site of renin expression and secretion is the renal juxtaglomerular cell, where its expression is tightly regulated by physiological cues. An evolutionarily conserved transcriptional enhancer located 11 kb upstream of the human RENIN gene has been reported to markedly enhance transcription in renin expressing cells in vitro. However, its importance in vivo remains unclear. We tested whether this enhancer is required for appropriate tissue-and cell-specific expression, or for physiological regulation of the human RENIN gene. To accomplish this, we used a retrofitting technique employing homologous recombination in bacteria to delete the enhancer from a 160-kb P1-artificial chromosome containing human RENIN, two upstream genes and one downstream gene, and then generated two lines of transgenic mice. We previously showed that human renin expression in transgenic mice containing the wild type construct is tightly regulated as is expression of the linked genes. Deletion of the enhancer had no effect on tissue-specific expression of human RENIN, but using the downstream gene as an internal control, found that human RENIN mRNA levels were 3-10-fold decreased compared with constructs containing the enhancer. Despite this decrease in expression, renin protein remained localized to renal juxtaglomerular cells and was appropriately regulated by cues that either increase or decrease expression of renin. Our results suggest that sequences other than the enhancer may be necessary for tissue-specific, cell-specific, and regulated expression of human RENIN.Renin is the first and rate-limiting aspartyl protease in the renin-angiotensin system (RAS) 2 cascade that leads to the production of angiotensin-II (Ang-II) by the consecutive cleavage of angiotensinogen by renin and angiotensin-I by angiotensin converting enzyme. Ang-II is an important regulator of cardiovascular function, stimulating vasoconstriction, cardiac output, aldosterone synthesis, and sympathetic activity, thereby directly and indirectly enhancing peripheral vascular resistance and renal tubular water and salt reabsorption. The critical importance of the RAS is evidenced by gene targeted ablation of the RAS genes in mice. The elimination of any RAS gene in mice causes cardiovascular consequences that include hypotension and renal insufficiency, and developmental consequences including postnatal lethality (1-4). The cardiovascular and developmental defects can be complemented in mice by substitution of the mouse RAS with their human orthologs (5) or by targeted expression of Ang-II (6). In humans, genetic defects in the RAS were reported to cause renal tubular dysgenesis, hypotension, and early stillbirth (7). Consequently, both the mouse and human genetic data illustrate the importance of the system both developmentally and in adults.Renin is primarily expressed in renal juxtaglomerular (JG) cells in the wall of the af...

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confidence: 99%

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

Zhoux

Davis

2006

Journal of Biological Chemistry

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“…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. 1,6 In addition, renal artery stenosis in adult kidneys also induces an expansion of renin-producing cells along preglomerular vessels. 7,8 It is not clear if these effects of insufficient kidney perfusion are transduced by mechanical signals or metabolic signals.…”

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confidence: 99%

“…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.…”

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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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“…43 Notably, AT1R or Sox17 mutations are causative factors in CAKUT in humans. 44,45 Whether structural maldevelopment of the medulla affects vasa recta formation or defects in vascular development account for decreased size of the medulla remains to be determined. Regardless, aberrant medullary microcirculation may have a major role in how fetal reprogramming results in postnatal diseases such as hypertension and progressive kidney disease.…”

Section: Do Not Distributementioning

confidence: 99%

Development of the kidney medulla

Song

Yosypiv

2012

Organogenesis

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Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis

Cited by 256 publications

References 23 publications

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

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

Development of the kidney medulla

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