Nonproteinuric Diabetes-Associated Nephropathy in the Cohen Rat Model of Type 2 Diabetes

Abstract

The Cohen diabetic rat is an experimental model reminiscent of human type 2 diabetes. The aim of this study was to characterize the development of end-organ damage in this model. Cohen diabetic sensitive (CDs) and Cohen diabetic resistant (CDr) rats were fed regular diet or a diabetogenic diet. Glucose tolerance, renal function, and renal and retinal histology were studied at set intervals. CDs fed diabetogenic diet were the only strain that expressed the diabetic metabolic phenotype. In this strain, urinary protein excretion did not increase with the development of diabetes, but plasma urea and creatinine levels increased and creatinine clearance decreased. Light microscopy revealed in CDs enlarged glomeruli with increased mesangial matrix and thickening of the glomerular capillary wall; electron microscopy demonstrated thickened basement membrane and mesangial abundance. There was increased staining for type IV collagen in glomeruli and interstitium of CDs. The retinas of diabetic CDs demonstrated pathology consistent with nonproliferative diabetic retinopathy. The histological findings in the kidneys, the absence of proteinuria, the impairment in glomerular filtration, and the development of retinopathy in CDs are consistent with diabetes-associated nephropathy that is similar to a nonalbuminuric type of nephropathy associated with type 2 diabetes in humans. Diabetes 54:1487-1496, 2005 T he Cohen diabetic rat is an experimental rodent model reminiscent of human type 2 diabetes (1,2). The model consists of two strains: the Cohen diabetic sensitive (CDs) rat, which invariably develops diabetes when fed a diabetogenic diet, and the Cohen diabetic resistant (CDr) rat, which remains normoglycemic even when fed a similar diet (1). The original colony was established over 30 years ago (2). We recently rebred animals from the original colony and characterized the metabolic phenotype of the new colony (1). We subsequently set forth to investigate whether target organ damage related to diabetes develops in this model. Because nephropathy is among the most common and morbid complications of diabetes, our focus was on the kidney.Earlier studies on the renal phenotype of this model placed much emphasis on histopathology, but paid little or no attention to kidney function (3-13). Preliminary studies by our group indicated that in the CDs strain, an unusual type of nephropathy evolves with no significant proteinuria but with progressive impairment of kidney function. In the current study, we present the results of our investigation on the development of end-organ damage in animals from the new Cohen diabetic rat colony. We provide histopathological evidence of the diabetes-related renal and retinal lesions and characterize functional aspects of the diabetic renal injury in this model. We demonstrate that the CDs is an experimental model of type 2 diabetes that develops a nonproteinuric type of diabetic nephropathy. RESEARCH DESIGN AND METHODSThe animals that were used in this study were male CDs and CDr rats that had been r...

Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome

“…This is in line with results from clinical studies demonstrating that in addition to hyperglycemia, other metabolic factors and blood pressure are involved in the manifestation and progression of retinopathy in humans. 4,54,55 In this regard, SHR/N-cp together with other non-STZ-based rat models [56][57][58][59][60][61][62][63][64] are useful tools to dissect the complexity of causative factors and disease mechanisms contributing to the varying spectrum of diabetic retinopathy. 55 Studies in these models have indeed revealed the contrasting impairment of the retina in the presence of cardiometabolic risk factors.…”

Is Nonalbuminuric Renal Insufficiency in Type 2 Diabetes Related to an Increase in Intrarenal Vascular Disease?

“…Recently an animal model of type 2 diabetic normoalbuminuric renal insufficiency has been described (31). The Cohen diabetic rat is known to develop progressive impairment in renal function with morphological changes that are typical of diabetic glomerulosclerosis but without proteinuria.…”

β-Glycosphingolipids improve glucose intolerance and hepatic steatosis of the Cohen diabetic rat

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