FVB mouse genotype confers susceptibility to OVE26 diabetic albuminuria

Abstract

PN. FVB mouse genotype confers susceptibility to OVE26 diabetic albuminuria. Am J Physiol Renal Physiol 299: F487-F494, 2010. First published July 7, 2010 doi:10.1152/ajprenal.00018.2010 diabetic mice on the inbred strain FVB are a valuable model of diabetic nephropathy that excretes the highest amount of urine albumin of all diabetic mouse models. Crossing of OVE mice to C57BL6 or DBA2 mice reduced albuminuria 17-fold in F1 diabetic offspring without reducing diabetes. When comparing renal histology of OVE mice on the FVB background to F1 C57BL6 crosses, we found that the F1 kidneys had significantly smaller glomeruli, much less albumin accumulation in tubules, reduced mesangial matrix expansion, and less interstitial fibrosis. A genome scan of 108 OVE-positive N2 offspring for albuminuria revealed one significant peak on chromosome 11 and nearly significant peaks on chromosomes 9, 13, and 19. Homozygosity for the FVB genotype for peaks on chromosomes 11, 13, or 19 increased albuminuria. Homozygosity for the chromosome 9 peak reduced albuminuria. Combined homozyogosity for the peaks on chromosomes 11, 13, and 19 increased albuminuria over 12-fold and accounted for Ͼ70% of the difference between OVE mice on the FVB vs. the F1 background. These loci contain sequences important to susceptibility to diabetic albuminuria. diabetic nephropathy; genetic background; urine albumin excretion DIABETIC NEPHROPATHY (DN) is the most common cause of end-stage renal disease (11) and is associated with significantly increased mortality. In patients with type 1 diabetes, ϳ30% will manifest DN (13). A major characteristic of DN is albuminuria, and this feature is a predictor for progression toward renal failure. Reducing urine albumin is an important therapeutic goal for preventing decline in renal function (21).Studies of familial aggregation, racial and ethnic comparisons, and linkage analysis have indicated a significant genetic component to DN (3,8), and currently there are major human genome-wide studies underway to identify genetic loci in diabetic populations that confer susceptibility to DN (14). However, the identification of specific genes underlying DN in humans has proven difficult, expensive, and time consuming. This is due in part to the heterogeneity of the genome of human populations as well as uncontrolled environmental factors. Inbred strains of rodents are not encumbered by the difficulties of genetic heterogeneity or environmental variation. Since quantitative trait loci for many complex traits are concordant among mice, rats, and humans, genome scans in animal models are relevant to human diseases (17, 18) and can provide more rapid results.The OVE26 (OVE) mouse carries a transgene overexpressing calmodulin in pancreatic ␤ cells, resulting in early onset of type I diabetes (6). At present, it is the diabetic mouse line which manifests by far the most profound albuminuria (20, 25). These mice have been maintained on an inbred FVB background. The purpose of the current study was to determine whether the FVB b...

TEM Stereometric Analyses of Glomeruli in Aging OVE26 Transgenic Diabetic Mice

“…By 150 days of age, kidney weights exceed controls by ∼79%, but like their human counterparts [11], body weights in diabetics and age-matched controls are not markedly different. In addition, albuminuria is a well-known clinical hallmark of human diabetes mellitus [11], and OVE26 mice exhibit by far the most profound UAE of any murine model of diabetes [6]. …”

“…Importantly, these mice frequently live 15 months or longer, and exhibit a wide array of functional [2] and morphological chronic complications of human DN [2,3,4,5]. Although OVE26 mice are long-lived models of DN, interestingly, they manifest by far the most profound urinary albumin excretion (UAE) of any available mouse line [6]. …”

Rodent models of diabetic nephropathy: their utility and limitations

“…33 Male heterozygous OVE26 diabetic mice are bred with female wild-type FVB mice, and the resulting OVE26 mice exhibit significant albuminuria by 2 months of age. Albuminuria increases progressively with age and is markedly increased at 9 months of age (average urinary albumin excretion exceeding 15 mg/24 hr).…”

Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1 diabetes

“…13 OVE26 animals exhibit severe albuminuria and, at later stages, renal structural changes resembling human DN. 13,25 Male OVE26 mice on the FVB background and control FVB mice were obtained from the Jackson Laboratories (n ¼ 6 in each group) were studied at 8 weeks of age.…”