Intrarenal Oxidative Stress and Augmented Angiotensinogen are Precedent to Renal Injury in Zucker Diabetic Fatty Rats

The Zucker diabetic fatty (ZDF) rat is a model of type II diabetes and metabolic syndrome based on impaired glucose tolerance caused by the inherited insulin-resistance gene. The ZDF rat exhibits progressive nephropathy; however, the detailed mechanisms have remained unclear. This study was performed to examine the possible involvement of enhanced intrarenal angiotensinogen in the development of renal injury in ZDF rats. Genetic pairs of male ZDF rats and control lean rats (N=6 each) were maintained from 12 to 17 weeks of age. At 17 weeks of age, fasting blood glucose and urinary 8-isoprostane levels were significantly higher in ZDF rats compared with the controls. Systolic blood pressure progressively increased in ZDF rats from 120+/-1 to 137+/-1 mmHg during this period. In contrast, systolic blood pressure did not increase in the controls. Kidney angiotensinogen protein levels were significantly increased in ZDF rats compared with the controls (1.83+/-0.34 vs. 1.00+/-0.17, relative ratio). Expression of angiotensin II type 1a receptor mRNA was similar between these groups. The measured indices of renal damage in the present study (glomerular sclerosis, interstitial expansion, glomerular macrophage infiltration, and renal arterial proliferation) were not significantly increased at this stage in ZDF rats. However, we previously showed that the increased reactive oxygen species-related angiotensinogen enhancement plays an important role in the development of renal injury in a genetic salt-sensitive hypertension. Thus, the present data suggest that elevated reactive oxygen species and reactive oxygen species-associated augmentation of intrarenal angiotensinogen may initiate the development of renal injury in ZDF rats.