Abstract 134: Temporal Characterization of the Development Diabetic Induced Renal Disease in Strains of Goto-kakizaki Rats
End stage renal disease is a major problem of patients suffering from diabetes and the development of novel therapeutic drugs are needed to help prevent the progression of diabetic nephropathy (DN). However, little is known about the pathogenesis of DN because the lack of an appropriate rodent model that develops progressive chronic kidney disease and renal histopathology seen in diabetic patients. The current study characterized the temporal changes in renal hemodynamics during the development of renal disease in Goto-Kakizaki (GKControl) diabetic rats that are resistant to the development of renal disease and a genetically modified GK substrain (GKT2DN) that is far more susceptible to the development of DN. Both strains have similar elevations in plasma glucose levels by 3 months of age. The GKT2DN strain exhibited hyperfiltration reflected by an increase in GFR (measured by the clearance of FITC-inulin) at 6 months of age compared to GKControl rats. GKT2DN rats develop progressive proteinuria that increases from 39±4 to 524±64 mg/day and a decline in GFR (from 934±68 to 370±50 μL/min/gkw) (n=21) as the rats age from 3 to 18 months of age. In contrast, proteinuria only increased to 194±33 mg/day in GKControl rats and GFR remained relatively unaltered over the same time period (n=19). The kidneys of GKT2DN rats exhibited mesangial expansion, glomerulosclerosis, and interstitial and renal fibrosis characteristic of patients with diabetes while the GKControl strain did not. We next utilized microarray analysis to identify differences in gene signaling pathways in the renal cortex between the two strains at the early onset of renal disease (6 months of age). We found 1266 genes that were differential expressed in signaling pathways associated with inflammation, cell proliferation, molecular transport and apoptosis between the susceptible strain (GKT2DN) versus the resistant strain (GKControl). In summary, these data indicate that the GKT2DN rat exhibits hyperfiltration and progressive proteinuria and chronic kidney disease and is a useful model to explore new therapies and genetic factors in the pathogenesis of DN.