Mouse Models of Diabetic Nephropathy

Abstract

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...

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

“…It is possible that the mice adapted to the loss of one copy of the SOD2 gene by upregulating other antioxidant defense systems, although in non-stressed control SOD2 +/− mice no changes were found in antioxidant enzymes in a survey of several mouse organs (Van Remmen et al, 1999). While these results were at first unexpected, these same animals had no evidence of diabetic nephropathy or retinopathy [data available on www.amdcc.org, and reviewed in (Breyer et al, 2005)]. …”

“…The reasons for this failure are likely multiple, and include the absence of genetic susceptibility genes and a short life-span (Breyer et al, 2005). Since SOD mimetics can both decrease rodent nerve conduction deficits (Coppey et al, 2001) and restore blood flow (Schnackenberg and Wilcox, 2001) in diabetes, we hypothesized that decreased expression of SOD would accelerate oxidative injury in hyperglycemia and magnify DN.…”

Sucrose intake and fasting glucose levels in 5-HT1A and 5-HT1B receptor mutant mice

“…In order to avoid distress evoked by prolonged fasting, a separate group of naïve animals was deprived of food on the morning of testing [18]. In accordance with the National Institutes of Health standard protocol, animals were fasted between 07:00 and 13:00 and blood was drawn at 13:00.…”

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice

“…We employed the db/db mouse for these studies, one of the most widely used models of type 2 diabetes mellitus (Sharma et al 2003;Tesch and Lim 2011). Although this model has shortcomings (Breyer et al 2005;Brosius et al 2009;Breyer 2012), these mice do recapitulate early renal consequences of systemic hyperglycemia, such as the development of glomerular hyperfiltration (elevated glomerular filtration rate (GFR) above the normal filtration rates), increased albuminuria and some histopathologic changes. Metabolomic comparisons of urinary metabolites show similarities between this mouse model and type 2 diabetic humans (Salek et al 2007).…”