PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST, ROSIGLITAZONE, PROTECTS AGAINST NEPHROPATHY AND PANCREATIC-ISLET ABNORMALITIES INZUCKER FATTY RATS

Rosiglitazone (BRL 49653), a peroxisome proliferator-activated recepto r-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent , was given in the diet (50 mu mol/kg of diet) to male Zucker rats age s 6-7 weeks for 9 months (prevention group). In this treatment mode, r osiglitazone prolonged the time to onset of proteinuria from 3 to 6 mo nths and markedly reduced the rate of its subsequent progression. Prog ression was also retarded when treatment was commenced (intervention g roup) after proteinuria had become established (4 months; ages 24-25 w eeks). In either treatment mode, rosiglitazone normalized urinary N-ac etyl-beta-D-glucosaminidase activity, a marker for renal proximal tubu lar damage, and ameliorated the rise in systolic blood pressure that o ccurred coincidentally with the development of proteinuria in Zucker f atty control rats. The renal protective action of rosiglitazone was ve rified morphologically. Thus in the prevention group there was an abse nce of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvil li on the tubular epithelium, and varying degrees of chronic interstit ial nephritis. An intermediate pathology was observed in the intervent ion group. Also, pancreatic islet hyperplasia, ultrastructural evidenc e of P-cen work hypertrophy, and derangement of a-cell distribution wi thin the islet were prominent features of Zucker fatty control rats, b ut these adaptive changes mere ameliorated (intervention group) or pre vented (prevention group) by rosiglitazone treatment. These data demon strate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the developmen t and progression of renal injury and the adaptive changes to pancreat ic islet morphology caused by sustained hyper-insulinemia.