Expression of NG,NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers.
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.


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.
Onozato
Maristela L
ML
Division of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan.
Tojo
Akihiro
A
Leiper
James
J
Fujita
Toshiro
T
Palm
Fredrik
F
Wilcox
Christopher S
CS
D000581:Amidohydrolases / Q000235:genetics*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D009399:Nephrons / Q000187:drug effects / Q000201:enzymology*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D011484:Protein-Arginine N-Methyltransferases; D000581:Amidohydrolases; C059999:dimethylargininase; D000077333:Telmisartan