Expression of N~G,N~G-Dimethylarginine Dimethylaminohydrolase and Protein Arginine N-Methyltransferase Isoforms in Diabetic Rat Kidney: Effects of Angiotensin II Receptor Blockers

摘要

OBJECTIVE-The nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) is generated by protein arginine N-methyltransferase (PRMT)-1 and is metabolized by N~G,N~G-dimethylarginine dimethylaminohydrolase (DUAH). We tested the hypothesis that increased serum ADMA (S_(ADMA)) in the streptozotocin (STZ)-induced diabetic rat model of diabetes is mediated by an angiotensin receptor blocker-sensitive change in DDAH or PRMT expression. RESEARCH DESIGN AND METHODS-Data were compared from four groups of rats: sham-injected controls, untreated STZ-induced diabetic rats at 4 weeks, STZ-induced diabetic rats administered the angiotensin II (Ang II) receptor blocker telmis-artan for 2 weeks, and control rats administered telmisartan for 2 weeks. RESULTS-Immunostaining and Western blotting of microdis-sected nephron segments localized DDAH I in the proximal tubules and DDAH II in the glomeruli, afferent arterioles, macula densa, and distal nephron. Renal Ang II and S_(ADMA) increased with diabetes but were normalized by 2 weeks of telmisartan. DDAH I expression was decreased in diabetic kidneys, while DDAH II expression was increased. These changes were reversed by telmisartan, which also reduced expression of PRMT-1 and -5. Telmisartan increased expressions of DDAH I but decreased DDAH II in Ang II-stimulated kidney slices ex vivo. CONCLUSIONS-Renal Ang II and S_(ADMA) are increased in insulinopenic diabetes. They are normalized by an Ang II receptor blocker, which increases the renal expression of DDAH I, decreases PRMT-1, and increases renal NO metabolites.