Comparison of the Development Diabetic Induced Renal Disease in Strains of Goto-Kakizaki Rats

Abstract

This study compared temporal changes in renal hemodynamics, proteinuria and the development of renal disease in Goto-Kakizaki (GK) type II diabetic rats that are resistant to the development of diabetic nephropathy and a genetically modified GK substrain (T2DN) carrying the mitochondrial genome and other alleles from Fawn hooded-hypertensive (FHH) rats is more susceptible to the development of renal injury. Both GK and T2DN rats were diabetic (>250 mg/ dL) and blood glucose levels were not significantly different at 3, 6 and 18 months of age. Blood pressure was also similar in both strains at all 3 ages. Renal blood flow (RBF) was 45% higher in 3 month old T2DN rats than GK rats but glomerular filtration rate (GFR) was similar. T2DN rats exhibited a progressive increase in proteinuria from 41 ± 2 to 524 ± 50 mg/day and 57% fall in GFR as they aged from 3 to 18 months of age. In contrast, proteinuria only increased to 162 ± 31 mg/day in GK rats and GFR remained unaltered. The kidneys from 18 month old T2DN rats exhibited severe glomerulosclerosis, interstitial fibrosis and tubular necrosis while kidneys from GK rats did not. Plasma creatinine levels were 2.4 fold higher in 18 month old T2DN than in GK rats. These data demonstrate that T2DN rats develop most of the features of diabetic nephropathy including progressive proteinuria and chronic kidney disease whereas the closely related GK strain does not, even though blood pressure and the level of hyperglycemia are similar.