Abstract P208: Effect of Rosiglitazone on Renal Neprilysin Activity and Protein Expression in Db/db Diabetic Mice

Abstract

Alteration in renin-angiotensin system has been implicated in the pathophysiology of diabetic kidney disease. The deleterious actions of angiotensin II (Ang II) could be antagonized by the formation of Ang (1-7) partly generated by the actions of angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP). NEP is a member of the zinc-containing metallopeptidase family, and has a main role in the degradation of several peptides, including natriuretic peptides, bradykinin, amyloid beta, and Ang I. Our previous studies demonstrated increased shedding of renal ACE2 in db/db mouse model of type 2 diabetes. We also showed that treatment with the PPAR_ agonist, rosiglitazone normalized hyperglycemia, decreased urinary ACE2 and attenuated albuminuria in db/db mice. The aim of the study was to test the hypothesis that hyperglycemia down-regulates renal NEP in db/db diabetic mice and that treatment with rosiglitazone will normalize renal NEP expression and activity. Seven-week-old db/db male mice were subjected to rosiglitazone treatment (20 mg/kg/day) for 10 weeks. Treatment with rosiglitazone significantly lowered blood glucose levels in db/db mice (p<0.001). Western blot analysis and immunohistochemistry demonstrated a significant decrease in renal and urinary NEP protein expression in 17wk db/db mice compared to lean control mice (p<0.0001). Treatment of db/db mice with rosiglitazone attenuated albuminuria, increased renal NEP protein expression and activity. In conclusion, the renoprotective effects of rosiglitazone could be mediated by up-regulation of renal NEP expression and activity in db/db mice. Alteration in the balance between Ang II and Ang (1-7) forming enzymes could contribute to the development of albuminuria in db/db diabetic mice.