Chronic ETA Receptor Blockade Prevents the Progression of Renal Injury in Diabetic Dahl Salt‐sensitive (SS) Rats

The endothelin (ET) system has been shown to play an important role in the development and progression of diabetic nephropathy (DN) via an ETA receptor mediated inflammatory response. Tumor necrosis factor‐alpha (TNF‐α) is inflammatory cytokine that has been used as a marker of chronic renal disease. Preliminary studies from our laboratory indicate that the induction of diabetes in Dahl salt‐sensitive (SS) rats promotes the development DN that was associated with an increase in ET‐1 excretion. Therefore, the present study examined whether chronic ETA blockade with ABT‐627 prevents the progression of renal injury in diabetic SS rats with pre‐existing renal disease by decreasing renal TNF‐α levels. After 3 weeks of diabetes (STZ, 50 mg/kg, i.p.), proteinuria increased to 375±74 mg/day. The rats were then separated into two groups: (1) vehicle and (2) ABT‐627 (5mg/kg/day). After 6 weeks of ABT‐627 treatment, proteinuria was markedly decreased in diabetic SS rats versus vehicle treated rats without any changes in arterial pressure (289±17 vs. 371±30 mg/day, respectively). The expression of the TNF‐α signaling pathway in the renal cortex was significantly reduced in ABT‐627‐ treated diabetic SS rats compared to the values observed in vehicle treated rats. These findings indicate that the prevention of progressive proteinuria with chronic ETA blockade was associated with a decrease in the renal TNF‐α pathway.