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Expression of N^G,N^G-Dimethylarginine Dimethylaminohydrolase and Protein Arginine N-Methyltransferase Isoforms in Diabetic Rat Kidney

Effects of Angiotensin II Receptor Blockers

¹ Division of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan
² Division of Nephrology and Hypertension, Cardiovascular Kidney Hypertension Institute, Georgetown University, Washington, DC
³ Centre for Clinical Pharmacology and Therapeutics, British Heart Foundation Laboratories, University College London, London, U.K

Address correspondence and reprint requests to Christopher S. Wilcox, MD, PhD, Division of Nephrology and Hypertension, Georgetown University Medical Center, 6PHC, Suite F6003, 3800 Reservoir Rd., NW, Washington, DC 20007. E-mail: wilcoxch{at}georgetown.edu

Key Words: ADMA, asymmetric dimethylarginine • Ang II, angiotensin II • ARB, Ang II receptor blocker • AT₁-R, Ang II type 1 receptor • CCD, cortical collecting duct • DDAH, dimethylarginine dimethylaminohydrolase • eNOS, endothelial nitric oxide synthase • IMCD, inner medullary collecting duct • L-NMMA, N^G-monomethyl-L-arginine • NOS, NO synthase • NOx, NO metabolite • PRMT, protein arginine N-methyltransferase • SDMA, symmetric dimethylarginine • STZ, streptozotocin • TBST, Tris-buffered saline containing 0.1% Tween 20

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 (DDAH). 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 telmisartan for 2 weeks, and control rats administered telmisartan for 2 weeks.

RESULTS—Immunostaining and Western blotting of microdissected 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.

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