Abstract

The inbred obese Zucker (ZDF/Gmi, fa/fa) rat develops severe hyperglycemia and also exhibits severe renal disease. In this study, we compared the relative benefits of long-term treatment with angiotensin-converting enzyme inhibition (ACEI) to a peroxisome proliferator-activated receptor γ (PPARγ) agonist. Four groups of obese inbred Zucker rats were studied over a 6-month observation period; untreated animals, rats treated with ACEI alone, rats treated with PPARγ agonist alone, and rats treated with a combination of ACEI and PPARγ agonist. PPARγ agonist treatment normalized plasma glucose and led to massive increases in body weight. Both ACEI and PPARγ agonist were effective in reducing the proteinuria and glomerular and tubular kidney damage. However, the PPARγ agonist exerted superior renal protection compared with ACEI, in this model of spontaneously occurring chronic renal disease in the diabetic, obese inbred Zucker rat. Of note, although ACEI lowered blood pressure, there was no difference in glomerular blood pressure in any group at the end of the study. The glomerular filtration rate (GFR) was improved by ACEI with a borderline effect of PPARγ agonist alone. A mild additive protection on GFR and tubulointerstitial damage was seen with the combination. Based on the literature it is likely that the superior protection by PPARγ agonist versus glomerular and tubular damage as well as proteinuria extends beyond glycemic and lipidmic control and also reflects direct, protective intrarenal actions of the PPARγ agonists.