Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats

Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agen ts. Herein, we provide evidence showing that troglitazone, one of the TZD c ompounds, is able to prevent glomerular dysfunction in diabetic rats throug h a novel mechanism independent of its insulin-sensitizing action. We exami ned the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats, Troglitazone was able to prevent not only diabetic glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transfo rming growth factor-beta 1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically an increase in diacyglycerol (DAG) cont ents and the activation of the protein kinase C (PKC)-extracellular signal- regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesang ial cells cultured under high glucose conditions was also inhibited by trog litazone. Troglitazone enhanced the activities of DAG kinase, which could m etabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly; piogl itazone, another TZD compound without alpha-tocopherol moiety in its struct ure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These re sults may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent glomerular dysfunction through the inhibition of the DAG-PKC-ERK pathway.