Reporter gene recombination in juxtaglomerular granular and collecting duct cells by human renin promoter-Cre recombinase transgene

Castrop, Hayo; Oppermann, Mona; Weiss, Yvonne; Huang, Yuning; Mizel, Diane; Lü, Huiyan; Germain, Stéphane; Schweda, Frank; Theilig, Franziska; Bachmann, S.; Briggs, Josephine P.; Kurtz, Armin; Schnermann, Jürgen

doi:10.1152/physiolgenomics.00302.2005

Cited by 14 publications

(11 citation statements)

References 32 publications

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“…Although more than one renin gene exists in mice, we believe that the expression pattern of the mouse renin-1d gene, which was used as a reporter in this study, is very similar to the expression of the human renin gene. 16,17 As anticipated, pVHL knockdown resulted in constitutive stabilization of HIF in renin-expressing cells in afferent arterioles and collecting ducts. The activation of the renin promoter in the collecting duct during kidney development is a known but unexplained phenomenon.…”

Section: Discussionsupporting

confidence: 52%

“…The activation of the renin promoter in the collecting duct during kidney development is a known but unexplained phenomenon. 17,18 These data, thus, do not support the hypothesis that hypoxia and HIF-dependent gene expression promote the phenotypic switch of vascular smooth muscle cells to renin-producing cells. In contrast, these findings suggest that HIF target genes and in particular, HIF-2-dependent genes suppress renin production.…”

Section: Discussionmentioning

confidence: 67%

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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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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 67%

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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“…Similarly, transgenic mice containing constructs consisting only of short hREN 5Ј-flanking regions fused to reporter genes generally failed to exhibit correct expression (48,49). One recent study fusing 12.2 kb of the hREN promoter including the KE to cre-recombinase exhibited cre activity in JG cells but also the renal medulla suggesting either some ectopic expression or the identification of a renal medullary lineage of renin expressing cells (50). In aggregate, these data suggest the proximal promoter may be necessary and sufficient to target renal JG cells, but that a combination of other sequences either upstream of the gene (e.g.…”

Section: Discussionmentioning

confidence: 96%

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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“…Standard protocol for reverse transcription was used. Real-time PCR (Roche) was performed as already described [3,33].…”

Section: Animal Experimentsmentioning

confidence: 99%

cAMP target sequences enhCRE and CNRE sense low-salt intake to increase human renin gene expression in vivo

Desch

Harlander

Neubauer

et al. 2011

Pflugers Arch - Eur J Physiol

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This study aimed to assess the role of cAMP target sequences enhancer cAMP response element (enhCRE) and cAMP and overlapping negative response element (CNRE) in the control of human renin gene (REN) in vivo. enhCRE and CNRE were silenced by mutations in a 12.2-kb human renin promoter fused to LacZ reporter gene. This construct was used to generate transgenic mice (RENMut-LacZ). The expression of the transgene was correctly targeted to the juxtaglomerular portions of renal afferent arterioles which express endogenous mouse renin. Therefore, enhCRE and CNRE do not seem to be relevant for the control of the cell-specific expression of the human renin gene. The β-adrenoreceptor agonist isoproterenol (10 mg/kg/day, for 2 days) stimulated the endogenous renin, but not the LacZ mRNA expression. Treatment of RENMut-LacZ mice with the angiotensin converting enzyme inhibitor (enalapril 10 mg/kg/day, for 7 days) or their crossing to angiotensin receptor type 1a knockout mice led to increased renin and LacZ mRNA levels. Renin expression was upregulated by low-salt diet (0.03% NaCl, for 10 days) and downregulated by high-salt diet (4% NaCl, for 10 days). In contrast, low-salt diet did not influence, while high-salt diet inhibited the expression of LacZ. In summary, enhCRE and CNRE appear to be necessary for the transactivation of the human renin gene through β-adrenoreceptors and by low-salt diet. Our data also suggest that different intracellular mechanisms mediate the effect of low- and high-salt intake on renin expression in vivo.

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Reporter gene recombination in juxtaglomerular granular and collecting duct cells by human renin promoter-Cre recombinase transgene

Cited by 14 publications

References 32 publications

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

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

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

cAMP target sequences enhCRE and CNRE sense low-salt intake to increase human renin gene expression in vivo

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