Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion

Background. Renal complications of long-term, poorly controlled type 2 diab etes mellitus include glomerulosclerosis and interstitial fibrosis. The ons et and progression of these complications are influenced by underlying path ophysiologies such as hyperglycemia, hypertriglyceridemia, and hypercholest erolemia. Troglitazone, a thiazolidinedione, has been shown to ameliorate t hese metabolic defects. However, it was not known whether therapeutic inter vention with troglitazone would prevent the onset and progression of glomer ulosclerosis. Methods. Sixty male ZDF/Gmi (TM) rats and 30 age-matched Zucker lean rats w ere in the study. The ZDF/Gmi (TM) rats were divided into two groups, one i n which blood glucose levels were uncontrolled (30 animals) and another (30 ) in which blood glucose was controlled via dietary administration of trogl itazone. Ten animals from each group were sacrificed at one, three, and six months into the study. The kidneys were harvested and processed for immuno staining with BM-CSPG, a marker for mesangial matrix. Images of 200 glomeru li per animal were captured using digital imaging microscopy, and the index of mesangial expansion (total area mesangium/total area of tuft) per glome rular section was measured. Results. The administration of troglitazone ameliorated the metabolic defec ts associated with type 2 diabetes mellitus. Moreover, the glomeruli from t issue sections of animals given troglitazone showed no mesangial expansion when compared with normoglycemic control animals, whereas the uncontrolled diabetic animals showed significant mesangial expansion at all time interva ls. Conclusions Therapeutic intervention with the thiazolidinedione troglitazon e halts the early onset and progression of mesangial expansion in the ZDF/G mi (TM) rat, preventing the development of glomerulosclerosis in this anima l model of type 2 diabetes mellitus.