title: Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats.
abstract: Peroxisome proliferator activated receptor-gamma (PPARgamma) ligands increase nitric oxide (NO) production and reduce systemic blood pressure. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which has two isoforms, DDAH-I and -II. In order to elucidate the mechanism whereby PPARgamma ligands affect NO metabolism, their effects on the DDAH-ADMA pathway were investigated. Six-week-old male Wister-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were maintained with or without pioglitazone (PIO), a PPARgamma ligand. After 4 weeks, serum ADMA levels and urinary daily NO excretion were analyzed. Tissue DDAH expression was examined by real-time polymerase chain reaction (PCR), immunoblotting, and immunohistochemistry. The results showed that PIO decreased serum ADMA and increased urinary NO excretion in both WKY and SHR. Also in both strains, the expression level of DDAH-II in the kidney was increased at transcriptional levels, although the DDAH-I level was unaffected. PIO lowered blood pressure in SHR, but not in WKY. We also demonstrated that PIO induced DDAH-II protein expression in Marbin-Dubin Canine Kidney (MDCK) cells, a renal tubular cell line. In conclusion, a PPARgamma ligand was here found to increase NO production partly by upregulating tissue DDAH-II expression and decreasing systemic ADMA levels. This mechanism constitutes a direct action on renal tubular cells, but is less likely to be responsible for the blood pressure-lowering effects of PPARgamma ligands. Since ADMA is one of the risk factors for cardiovascular events, this study provides compelling evidence that PPARgamma ligands have the potential for reducing cardiovascular risks.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. swakino@sc.itc.keio.ac.jp
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Satoru
authors.initials: S
authors.lastname: Tatematsu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takamatsu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanda
authors.forename: Koichiro
authors.initials: K
authors.lastname: Homma
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Naoki
authors.initials: N
authors.lastname: Sugano
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D002460:Cell Line; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006710:Homocysteine / Q000097:blood; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007684:Kidney Tubules / Q000166:cytology / Q000201:enzymology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012964:Sodium / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D006710:Homocysteine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D012964:Sodium; D000581:Amidohydrolases; C059999:dimethylargininase; D000077205:Pioglitazone