Increased Expression of Glutathione S- Transferase in Renal Proximal Tubules in the Early Stages of Diabetes: A Study of Type-2 Diabetes in the Akita Mouse Model

Diabetic nephropathy (DN) is a late diabetic complication that comprises progressively increasing albuminuria, declining GFR, and increased cardiovascular risk. Only a minority of patients with diabetes (25 to 40%) develop nephropathy, and there is evidence that heritable genetic factors predispose these "at-risk" individuals to DN. Comparing variability among inbred mouse strains with respect to a specific phenotype can model interhuman variability, and each strain represents a genetically homogeneous system with a defined risk for nephropathy. C57BL/6 mice, which are relatively resistant to DN, were mutagenized using N-ethyl-N-nitrosourea and screened for mutants that developed excess albuminuria on a sensitizing type 1 diabetic background contributed by the dominant Akita mutation in insulin-2 gene (Ins2 Akita ). Two of 375 diabetic G1 founders were found to exhibit albumin excretion rates persistently 10-fold greater than albumin excretion rates in nonmutagenized Ins2Akita controls. This albuminuria trait was heritable and transmitted to approximately 50% of Ins2 Akita G2 and G3 progeny, consistent with a simple, dominantly inherited trait, but was never observed in nondiabetic offspring. During the course of 1 yr, albuminuric Ins2 Akita G2 and G3 progeny developed reduced inulin clearance with elevated blood urea nitrogen and plasma creatinine. Glomerular histology revealed mesangial expansion, and glomerular basement membrane thickening as determined by electron microscopy was enhanced in diabetic mutant kidneys. Hereditary albuminuric N-ethyl-N-nitrosourea-induced mutants were redesignated as Nphrp1 (nephropathy1) and Nphrp2 (nephropathy2) mice for two generated lines. These novel mutants provide new, robust mouse models of DN and should help to elucidate the underlying genetic basis of predisposition to DN.

Section: Discussionsupporting

confidence: 92%

A Sensitized Screen of N-ethyl-N-nitrosourea–Mutagenized Mice Identifies Dominant Mutants Predisposed to Diabetic Nephropathy

Tchekneva¹,

Rinchik²,

Polosukhina³

et al. 2007

“…Furthermore, as described by others in previous studies, we observed mesangial expansion as sign of early diabetic glomerular alterations by both light and electron microscopic examination. 10,17,32,33 In addition, an increase of urinary albumin excretion was noted, indicative of some abnormality of glomerular permselectivity, but as in other studies in Ins2 ϩ/Ϫ mice, the increase in albumin excretion was mild. 16,17,32,34 Our BASIC RESEARCH www.jasn.org study shows that the glomerular abnormalities observed in Ins2 ϩ/Ϫ mice are enhanced in these mice when they lack A1AR.…”

Section: Discussionsupporting

confidence: 67%

Lack of A1 Adenosine Receptors Augments Diabetic Hyperfiltration and Glomerular Injury

Faulhaber-Walter¹,

Chen²,

Oppermann³

et al. 2008

Intraglomerular hypertension and glomerular hyperfiltration likely contribute to the pathogenesis of diabetic nephropathy, and tubuloglomerular feedback (TGF) has been suggested to play a role in diabetic hyperfiltration. A1 adenosine receptor (A1AR) null mice lack a TGF response, so this model was used to investigate the contribution of TGF to hyperfiltration in diabetic Ins2 ϩ/Ϫ Akita mice. TGF responses in Ins2 ϩ/Ϫ A1AR Ϫ/Ϫ double mutants were abolished, whereas they were attenuated in Ins2mice. GFR, assessed at 14, 24, and 33 wk, was approximately 30% higher in Ins2 ϩ/Ϫ than in wild-type (WT) mice and increased further in Ins2 ϩ/Ϫ A1AR Ϫ/Ϫ mutants (P Ͻ 0.01 versus both WT and Ins2 ϩ/Ϫ mice at all ages). Histologic evidence of glomerular injury and urinary albumin excretion were more pronounced in double-mutant than single-mutant or WT mice. In summary, the marked elevation of GFR in diabetic mice that lack a TGF response indicates that TGF is not required to cause hyperfiltration in the Akita model of diabetes. Rather, an A1AR-dependent mechanism, possibly TGF, limits the degree of diabetic hyperfiltration and nephropathy.

“…As seen with other models of DN in the C57BL/6J strain, albuminuria is not a prominent feature (10.23 Ϯ 2.73 g/24 h in diabetic mice versus 13.9 Ϯ 8.8 g/24 h in controls) (89). Renal immunopathologic studies show significant deposition of IgA in the glomeruli of Akita mice (88); however, given the association of IgA deposition in glomeruli of up to 20% of humans with diabetes (90) and rat models of diabetes, the significance of these findings is uncertain (91)(92)(93).…”

Section: Insulin-2 Akitasupporting

confidence: 55%

Mouse Models of Diabetic Nephropathy

Breyer¹,

Böttinger²,

Brosius³

et al. 2005

477

516

Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.J (1), with costs for care of these patients projected to be $12 billion/yr by 2010 (1). Despite the high prevalence of DN, only 20 to 40% of all diabetic patients are prone to developing kidney failure, and family-based studies suggest that a significant genetic component confers risk for DN (2-4). Studies of diabetic mice suggest that, like people, mice exhibit differential susceptibility to diabetes and renal and cardiovascular diseases (5-7). In mice, identification of a strain that is prone to disease provides the relevant discriminator rather than identification of an individual who is at risk for diabetic complications. However, in contrast to people, each inbred mouse strain represents a genetically homogeneous and readily replenished resource that is amenable to repeated experimental study.Biomedical experimentation in mice affords significant advantages over experimentation in other species. These advantages include the development of diverse and unique genetic resources, including completion of a detailed map of murine genomic sequence that is freely available through the internet, as well as Ͼ450 inbred strains of mice that have been generated over the past century, with each strain genetically being homogeneous and offering a unique array of phenotypes (8,9). The availability of murine embryonic stem cells has also provided the ability to disrupt the expression and function of specific preselected genes (10 -12). Finally, repositories of mice that bear multiple mutations that alter function in each known gene are gradually being assembled (13-15). These unique resources have the potential to significantly facilitate studies into the pathogenesis of disease in mice. Through the use of the unique genetic reagents that are available in mice (including knockouts and transgenics), the identification of a robust mouse model of DN should significantly facilitate understanding of the underlying genetic mechanisms that contribute to the development of DN in people as well as in mice. Establishment of a valid mouse model of DN should also facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans. Workin...