Isolation of the Mouse Ren-1C Gene and Characterization of Renin Gene Expression in Both ES-D3 Cells and Their Parental Mouse Strain.

Tanimoto, Koichi; Tamura, Kouichi; Sugiyama, Fumihiro; Murakami, Kazuo; Fukamizu, Akiyoshi

doi:10.1262/jrd.39.19

Cited by 5 publications

(3 citation statements)

References 30 publications

(37 reference statements)

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“…The resulting AT1a +/-F 5 mice were then intercrossed to generate the homozygous (AT1a -/-) mice. Concerning the genotype of the renin gene (17) in the AT1a -/-mice, Southern blot analysis was performed as described previously (18), and identity of the Ren-1C gene with that of C57Bl/6 mice was confirmed (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice

Hisada¹,

Sugaya²,

Yamanouchi³

et al. 1999

J. Clin. Invest.

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147

115

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Several lines of evidence show the importance of angiotensin II (AII) in renal injuries, especially when hemodynamic abnormalities are involved. To elucidate the role of AII in immune-mediated renal injury, we studied anti-glomerular basement membrane (GBM) nephritis in AII type 1a receptor (AT1a)-deficient homozygous (AT1a -/-) and wild-type (AT1a +/+ ) mice. A transient activation of the renin-angiotensin system (RAS) was observed in both groups of mice at around day 1. A renal expression of monocyte chemoattractant protein-1 (MCP-1) was transiently induced at six hours in both groups, which was then downregulated at day 1. In the AT1a +/+ mice, after RAS activation, the glomerular expression of MCP-1 was exacerbated at days 7 and 14. Thereafter, severe proteinuria developed, and the renal expressions of transforming growth factor-β1 (TGF-β1) and collagen type I increased, resulting in severe glomerulosclerosis and interstitial fibrosis. In contrast, glomerular expression of MCP-1, proteinuria, and tissue damage were markedly ameliorated in the AT1a -/-mice. Because this amelioration is likely due to the lack of AT1a, we can conclude that AII action, mediated by AT1a, plays a pathogenic role in anti-GBM nephritis, in which AII may contribute to the exacerbation of glomerular MCP-1 expression. These results suggest the involvement of AII in immune-mediated renal injuries. J. Clin. Invest. 103:627-635 (1999) MethodsAnimals. To obtain AT1a-deficient heterozygous (AT1a +/-) mice that have C57Bl/6 background, a germline chimera derived from TT2 embryonic stem (ES) cells with a targeted mutation of the AT1a gene as described previously (16), was backcrossed for five generations with C57Bl/6 mice. The resulting AT1a +/-F 5 mice were then intercrossed to generate the homozygous (AT1a -/-) mice. Concerning the genotype of the renin gene (17) in the AT1a -/-mice, Southern blot analysis was performed as described previously (18), and identity of the Ren-1C gene with that of C57Bl/6 mice was confirmed (Fig. 1). The AT1a -/-mice were then inbred to prepare the enough number of animals for the present study. As AT1a +/+ mice, C57Bl/6 mice were purchased from Japan Clea Co. (Tokyo, Japan). Only male mice at the age of 10 weeks were used for the studies. For the isolation of GBM and the preparation of anti-GBM antiserum (AS), ddy mice and Japanese white rabbits, respectively, were purchased from local breeders.Preparation of rabbit anti-GBM AS. The preparation of anti-GBM AS was performed as described by Nagai et al. (19). In brief, glomeruli were isolated by differential sieving from the mouse renal cortex and disrupted by sonication. The GBM was collected by centrifugation and emulsified with CFA (Difco Laboratories, Detroit, Michigan, USA). Anti-GBM AS was raised in Japanese white rabbits by repeated immunization with mouse GBM.Induction of anti-GBM nephritis. Anti-GBM nephritis was induced in the AT1a -/-and AT1a +/+ mice according to the method described by Nagai et al. (19). In brief, mice were immunized intraperitoneal...

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Section: Methodsmentioning

confidence: 99%

Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice

Hisada¹,

Sugaya²,

Yamanouchi³

et al. 1999

J. Clin. Invest.

Self Cite

147

115

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“…The most recent and exciting approach to hypertension is gene targeting: the disruption of a particular gene by homologous recombination in embryonic stem (ES) cells (130)(131)(132) (Fig. 7).…”

Section: Angiotensinogen-deficient Micementioning

confidence: 99%

Recent Advances in the Study of Renin and Angiotensinogen Genes: From Molecules to the Whole Body.

et al. 1995

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The renin-angiotensin system (RAS) plays a key role in the regulation of the circulation and is critically involved in the pathogenesis of several diseases, including hypertension. Renin is synthesized mainly in the kidney and is secreted into the bloodstream. It catalyzes the rate-limiting cleavage of substrate angiotensinogen, which is derived mainly from the liver, to generate angiotensin I. Renin and angiotensinogen genes have been isolated and their structure has been determined by the methods of molecular biology. Renin and angiotensinogen genes are expressed in many tissues, and the tissue-specific regulation of these genes has been studied. The existence of local RASs in contrast to the classical circulating RAS has been suggested, although their exact functional role remains to be determined. Recent molecular analyses have led to a detailed description of the transcriptional mechanism of the renin and angiotensinogen genes, and have made it possible to study the regulation of the expression of these genes in several physiological and pathological states. In addition, several types of transgenic animals have been developed to study the functional importance of the RAS in vivo. Transgenic mice with human renin and human angiotensinogen genes may be a good model of human hypertension. In such mice, the human genes are expressed in the normal tissue-specific pattern, the circulating RAS is activated, and blood pressure is high. Finally, angiotensinogen-deficient mice have also been developed by homologous recombination in mouse embryonic stem cells. These mice do not produce angiotensinogen in the liver. As a result, they have no plasma immunoreactive angiotensin I and are hypotensive. The profound hypotension in these mice indicates the importance of the RAS in maintaining pressure.

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“…It has been revealed that AngII plays an important role in the development of diabetic nephropathy, through its hemodynamic effect, or its effect on cell proliferation and/or inflammation (Singh et al, 2005;Suzuki et al, 2000). Moreover, clinical studies have demonstrated that the administration of angiotensin-converting enzyme (ACE) inhibitors or AngII receptor antagonists reduces proteinuria and slows the progression of diabetic nephropathy (Du et al, 1995;Tanimoto et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Gui Qi Mixture on the Progression of Diabetic Nephropathy in Rats

Zhang

Xie²,

Chen³

et al. 2006

Exp Clin Endocrinol Diabetes

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Huang Qi (root of Astragalus membranaceus) and Dang Gui ( Angelica sinensis), two of the most widely used herbs in traditional Chinese medicine, have been proven to be effective in the treatment of diabetes mellitus (DM) although the underlying molecular mechanisms are not fully elucidated. This study was designed to investigate the protective effect of Dang Gui and Huang Qi mixture (GQM) on the development of diabetic nephropathy in rats with streptozotocin (STZ)-induced DM and the possible underlying molecular mechanism. The diabetic animal model was made by a single intraperitoneal injection of STZ and then treated with GQM or benazepril. Blood glucose, triglyceride (TG), cholesterol (CHO), high density lipoprotein (HDL), serum creatinine (Scr), creatinine clearance rate (Ccr), blood urea nitrogen (BUN), urine beta (2)-microglobin (beta (2)-MG), kidney/body weight (K/B) ratio, glomerular area (GA), renal transforming growth factor-beta (1) (TGF-beta (1)) mRNA expression and blood and renal angiotensin II (AngII) expression were determined 8 weeks after the treatment. The blood glucose, CHO and TG levels, BUN, SCr, Ccr. K/B ratio, GA, the excretion of beta (2)-MG, renal TGF-beta (1) mRNA expression and blood and renal AngII expression were significantly increased while the HDL level was decreased 8 week after STZ injection. The changes in blood glucose, TG, CHO and HDL were reversed by GQM, not by benazepril, whereas the changes in other variables were reversed by both GQM and benazepril. Our results suggest that GQM alleviates the disorder in blood glucose and lipids, protects against the progression of renal nephropathy in diabetic rats, probably by inhibiting the expression of AngII and TGF-beta (1) mRNA.

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Isolation of the Mouse Ren-1C Gene and Characterization of Renin Gene Expression in Both ES-D3 Cells and Their Parental Mouse Strain.

Cited by 5 publications

References 30 publications

Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice

Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice

Recent Advances in the Study of Renin and Angiotensinogen Genes: From Molecules to the Whole Body.

Protective Effect of Gui Qi Mixture on the Progression of Diabetic Nephropathy in Rats

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