Interstrain Differences in Murine Daunomycin-Induced Nephrosis

Kimura, Masato; Takahasi, Hiroshi; Ohtake, Takayasu; Sato, Tadanobu; Hishida, Akira; Nishimura, Masahiko; Honda, Nishio

doi:10.1159/000187182

Cited by 23 publications

(17 citation statements)

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“…Prior data suggest that this trait is likely autonomous to the kidney: podocyte damage and glomerulosclerosis can be prevented by transient clipping of the renal artery during drug injection, suggesting that initial exposure to the anthracycline, rather than its metabolites, causes nephropathy (7,14). Moreover, interstrain and interspecies variations in drug levels do not correlate with susceptibility to nephrosis, further suggesting that variation in extrarenal drug metabolism is not a major contributor to renal injury (24,25). Because anthracyclines are naturally occurring antibiotic agents, we reasoned that this trait can serve as an excellent model for genetic investigation of podocyte susceptibility to environmental damage and that its elucidation would enable insight into pathways leading to nephropathy.…”

Section: Discussionmentioning

confidence: 99%

A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse

Zheng

Schmidt‐Ott

Chua

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The development of kidney disease is influenced by both genetic and environmental factors. Searching for models of glomerulopathy that display strong gene-environment interaction, we examined the determinants of anthracycline-induced nephropathy, a classic, strain-dependent experimental model applied to rodents in the past four decades. We produced three crosses derived from mice with contrasting susceptibility to doxorubicin (DOX) nephropathy and, surprisingly, we found that this widely studied model segregates as a single-gene defect with recessive inheritance. By genome-wide analysis of linkage, we mapped the trait locus to chromosome 16A1-B1 (DOXNPH locus) in all three crosses [peak logarithm of odds (lod) score of 92.7, P ‫؍‬ 1 ؋ 10 ؊65 ]; this interval represents a susceptibility locus for nephropathy. Gene expression analysis indicated that susceptibility alleles at the DOXNPH locus are associated with blunted expression of protein arginine methyltransferase 7 (Prmt7) on chromosome 8, a protein previously implicated in cellular sensitivity to chemotherapeutic agents (lod ‫؍‬ 12.4, P ‫؍‬ 0.0001). Therefore, Prmt7 expression serves as a molecular marker for susceptibility to DOX nephropathy. Finally, increased variation in the severity of kidney disease among affected mice motivated a second genome-wide search, identifying a locus on chromosome 9 that influences the severity and progression of nephropathy (DOXmod, peak lod score 4.3, P ‫؍‬ 0.0018). These data provide genetic and molecular characterization of a previously unrecognized Mendelian trait. Elucidation of DOX nephropathy may simultaneously provide insight into the pathogenesis of renal failure and mechanisms of cytotoxicity induced by chemotherapeutic agents.genetics

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Section: Discussionmentioning

confidence: 99%

A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse

Zheng

Schmidt‐Ott

Chua

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Several investigators suggested that the genetic background had a profound effect on the severity of renal injury (30,31). We generated AT1a-deficient mice using the TT2 ES cells that have a mixed genetic background of C57Bl/6 and CBA (16).…”

Section: Discussionmentioning

confidence: 99%

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

Hisada¹,

Sugaya²,

Yamanouchi³

et al. 1999

J. Clin. Invest.

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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“…The sensitivity to doxorubicin or the related substance daunomycin is variable in mice (10,11,28,48,54). In susceptible mice doxorubicin-induced nephrotic syndrome is followed by volume retention which is accounted for by enhanced activity of epithelial sodium channels (ENaC) and Na-K-ATPase in the collecting duct (15,34).…”

mentioning

confidence: 99%

Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome

Artunc

Nasir²,

Amann³

et al. 2008

American Journal of Physiology-Renal Physiology

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Doxorubicin-induced nephropathy leads to epithelial sodium channel (ENaC)-dependent volume retention and renal fibrosis. The aldosterone-sensitive serum- and glucocorticoid-inducible kinase SGK1 has been shown to participate in the stimulation of ENaC and to mediate renal fibrosis following mineralocorticoid and salt excess. The present study was performed to elucidate the role of SGK1 in the volume retention and fibrosis during nephrotic syndrome. To this end, doxorubicin (15 μg/g body wt) was injected intravenously into gene-targeted mice lacking SGK1 ( sgk1 −/−) and their wild-type littermates ( sgk1 +/+). Doxorubicin treatment resulted in heavy proteinuria (>100 mg protein/mg crea) in 15/44 of sgk1 +/+ and 15/44 of sgk1 −/− mice leading to severe nephrotic syndrome with ascites, lipidemia, and hypoalbuminemia in both genotypes. Plasma aldosterone levels increased in nephrotic mice of both genotypes and was followed by increased SGK1 protein expression in sgk1 +/+ mice. Urinary sodium excretion reached signficantly lower values in sgk1 +/+ mice (15 ± 5 μmol/mg crea) than in sgk1 −/− mice (35 ± 5 μmol/mg crea) and was associated with a significantly higher body weight gain in sgk1 +/+ compared with sgk1 −/− mice (+6.6 ± 0.7 vs. +4.1 ± 0.8 g). During the course of nephrotic syndrome, serum urea concentrations increased significantly faster in sgk1 −/− mice than in sgk1 +/+ mice leading to uremia and a reduced median survival in sgk1 −/− mice (29 vs. 40 days in sgk1 +/+ mice). In conclusion, gene-targeted mice lacking SGK1 showed blunted volume retention, yet were not protected against renal fibrosis during experimental nephrotic syndrome.

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Interstrain Differences in Murine Daunomycin-Induced Nephrosis

Cited by 23 publications

References 0 publications

A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse

A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse

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

Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome

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