Abstract P142: Progression of Diabetic Kidney Disease in the Type 2 Diabetic Nephropathy Rat Model

Abstract

Diabetic kidney disease (DKD) is a condition of hyperglycemia-induced renal injury that is one of the chief causes of end-stage renal disease (ESRD). Hypertension often affects people with type 2 diabetes and the combination of diabetes and hypertension is associated with high morbidity and mortality. Here we assessed the progression of DKD in the T2DN rat and tested if this model develops age dependent DKD similar to human patients. Sex difference in the development of DKD was further defined. For the assessment of disease progression, we used 12 weeks old (early stage) and >40 weeks old (late stage) male Wistar (non-diabetic control), Goto-Kakizaki (GK) and Type 2 Diabetic Nephropathy (T2DN) rats. At 12 weeks, male rats of type 2 diabetes background showed significant increases in blood glucose (374 ± 96 and 329 ± 45 vs. 280 ± 24 mg/dL, respectively for T2DN, GK vs. Wistar) and kidney to body weight ratio (10.05 ± 1.19 and 9.39 ± 0.78 vs. 7.31 ± 1.13, respectively). Aged male T2DN rats had significant increases in progressive albuminuria from 8 to 12 to >40 weeks of age (0.44 ± 0.16 vs 0.34 ± 0.17 vs 11.80 ± 5.67, respectively). T2DN rats also show significant reductions in the blood of the components of the renin-angiotensin-aldosterone system. There were significant changes in renal damage such as increases in percent of medullary protein casts and glomerulosclerosis (probability based; 1.2% vs 27.5%, respectively compared to age matched GK males). To explore the sexual dimorphisms in the development of DKD, we compared T2DN male and female rats when animals had the late stage of the disease (> 48 weeks old). Aged males had a significant impairment in their body’s response to sugar load compared to the females as assessed by both IP and oral gavage glucose tolerance tests. Aged male T2DN rats had increases in nephrin shedding in their urine (10,357 ± 4,866 vs 3,227 ± 2,918, respectively), which correlates with the dramatic differences in albuminuria (11.8 ± 5.7 vs. 0.98 ± 0.64 Alb/Cre ratio, respectively). In contrast, serum albumin levels were elevated in female T2DN rats. Therefore, we report here that T2DN rat develops renal and physiological lesions similar to those seen in patients with type 2 diabetes, and there is a dramatic sex difference in the progression of renal damage.