Diabetic nephropathy in type 2 diabetes mellitus: animal models with emphasis on recently developed corpulent rat strains

Abstract

Genetic background has recently been implicated as an important factor in the development of diabetic nephropathy in humans. Little is known about the natural history of renal disease in patients with type 2 (non-insulin-dependent) diabetes mellitus. Because toxins used in chemically induced models of diabetes may be associated with pathological renal changes, investigators have employed well-defined, genetically distinct animal models to study diabetic nephropathy. This review will focus on animal models of spontaneous type 2 diabetic nephropathy. No single animal model of diabetes corresponds exactly to the human disorder, nor develops renal changes identical to those seen in man. Rodents have been the most studied species with diabetic renal disease. The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat provides a unique model of obesity, type 2 diabetes and nephropathy. In addition, genetic controls for this rat, including the lean SHR/N-cp rat and the Wistar-Kyoto/NIH-corpulent (WKY/N-cp) rat, allow assessment of the role of hypertension and obesity in the pathogenesis of diabetic nephropathy. SHR/N-cp rats have abnormal glucose tolerance, hypertension, and develop a renal disease reminiscent of human diabetic nephropathy. WKY/N-cp rats are also obese and have hyperlipidaemia, but their glucose control is somewhat worse than that of the SHR/N-cp rat. In contrast, they do not have hypertension, the renal disease is less severe, and is less suggestive of the human pathology. Finally the LA/N-cp rat also carries the gene for obesity, and exhibits hyperlipidaemia. In contrast to the other two spontaneous models of obesity it does not exhibit hypertension or glucose intolerance. There is little evidence of renal disease in this model. The development of genetic models of obesity, hypertension and glucose intolerance provides a unique opportunity to make longitudinal observations on the natural history of diabetic nephropathy, and to test the various proposed mechanisms for the development of diabetic glomerulopathy, and the effects of various treatment modalities. Diversity in manifestations of diabetic renal disease in animals suggests the importance of genetic mechanisms in pathological outcomes.