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- Title
Expression of NG,NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers.
- Authors
Onozato ML; Tojo A; Leiper J; Fujita T; Palm F; Wilcox CS; Onozato, Maristela L; Tojo, Akihiro; Leiper, James; Fujita, Toshiro; Palm, Fredrik; Wilcox, Christopher S
- Abstract
<bold>Objective: </bold>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.<bold>Research Design and Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
ANIMAL experimentation; ANTI-infective agents; DIABETES; HETEROCYCLIC compounds; HYDROLASES; KIDNEYS; RATS; REFERENCE values; RESEARCH funding; TRANSFERASES; ANGIOTENSIN receptors; NEPHRONS; PHARMACODYNAMICS
- Publication
Diabetes, 2008, Vol 57, Issue 1, p172
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db06-1772