Contrasting differences of chronic endothelin A receptor blockade during the progression of renal injury in type‐1 and type‐2 diabetic nephropathy (689.3)

Abstract

Contrasting differences of chronic endothelin A receptor (ETA) blockade during the progression of renal injury in type‐1 and type‐2 diabetic nephropathy Denisha Spires1, Tiffani White2, Lateia Taylor2 and Jan M. Williams2. 1Tougaloo College, Tougaloo, MS, 2Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS 39216 The endothelin (ET) system has been shown to play an important role in the development and progression of diabetic nephropathy (DN) via the endothelin A (ETA) receptor. Preliminary studies from our laboratory indicate that the induction of diabetes (STZ, 50 mg/kg, i.p.) in Dahl salt‐sensitive (STZ‐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 STZ‐SS rats with pre‐existing renal disease. After 6 weeks of ABT‐627 (5mg/kg/day) treatment, proteinuria was markedly decreased in ABT‐627 treated STZ‐SS rats versus vehicle treated rats without any changes in arterial pressure (310±32 vs. 517±68 mg/day, respectively). The degree of glomerulosclerosis and renal interstitial fibrosis was significantly reduced in the kidneys of ABT‐627 treated STZ‐SS rats compared to vehicle STZ‐SS rats. We next determined whether treatment with ABT‐627 would be beneficial in a type‐2 diabetic model (T2DN rat) with pre‐existing renal injury. In contrast to the STZ‐SS study, ABT‐627 had no effect on the progression of renal injury in T2DN rats. In conclusion, these data indicate that treatment with an ETA receptor blocker prevents the progression of renal injury in type‐1 diabetes but not in type‐2 diabetes.Grant Funding Source: Supported by P20GM104357