Rosiglitazone improves aortic arginine transport, through inhibition of PKCalpha, in uremic rats.
Peroxisome proliferator-activated receptor (PPAR) agonists were shown to inhibit atherosclerosis through augmentation of endothelial nitric oxide synthase (eNOS) activity. In addition, rosiglitazone exerts a beneficial effect in chronic renal failure (CRF). Since l-arginine transport by CAT-1 (the specific arginine transporter for eNOS) is inhibited in uremia, we aimed to explore the effect of rosiglitazone on arginine transport in CRF. Arginine uptake by aortic rings was studied in control animals, rats, 6 wk following 5/6 nephrectomy (CRF) and rats with CRF treated with rosiglitazone. The decrease of arginine transport in CRF was prevented by rosiglitazone. Immunobloting revealed that CAT-1 protein was decreased in CRF but remained unchanged following rosiglitazone administration. Protein content of the membrane fraction of PKCalpha and phosphorylated CAT-1 increased significantly in CRF, effects that were prevented by rosiglitazone. PKCalpha phosphorylation was unchanged but significantly attenuated by rosiglitazone in CRF. Ex vivo administration of phorbol-12-myristate-13-acetate to rosiglitazone-treated CRF rats significantly attenuated the effect of rosiglitazone on arginine uptake. The decrease in cGMP response to carbamyl-choline (eNOS agonist) was significantly attenuated by rosiglitazone in CRF. Western blotting and immunohistochemistry analysis revealed that protein nitration was intensified in the endothelium of CRF rats and this was attenuated by rosiglitazone. In conclusion, rosiglitazone prevents the decrease in arginine uptake in CRF through both depletion and inactivation of PKCalpha. These findings are associated with restoration of eNO generation and attenuation of protein nitration and therefore may serve as a novel mechanism to explain the beneficial effects of rosiglitazone on endothelial function in uremia.
Ingbir
Merav
M
Department of Nephrology, Tel Aviv Sourasky Medical Center, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Schwartz
Idit F
IF
Shtabsky
Alexander
A
Filip
Irina
I
Reshef
Ran
R
Chernichovski
Tamara
T
Levin-Iaina
Nomi
N
Rozovski
Uri
U
Levo
Yoram
Y
Schwartz
Doron
D
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D027201:Cationic Amino Acid Transporter 1 / Q000378:metabolism; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014511:Uremia / Q000378:metabolism*
D027201:Cationic Amino Acid Transporter 1; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009569:Nitric Oxide; D001120:Arginine; D051571:Protein Kinase C-alpha