Arginine uptake is attenuated through modulation of cationic amino-acid transporter-1, in uremic rats.
Endothelial cell dysfunction (ECD) is a common feature of chronic renal failure (CRF). Defective nitric oxide (NO) generation due to decreased endothelial NO synthase (eNOS) activity is a crucial parameter characterizing ECD. L-arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine uptake, cationic amino-acid transporter-1 (CAT-1) acts as the specific arginine transporter for eNOS. Our hypothesis implies that CAT-1 is a major determinant of eNOS activity in CRF. We studied glomerular and aortic arginine uptake, CAT-1, and CAT-2 messenger ribonucleic acid (mRNA) expression, and CAT-1 protein in: (a) rats 6 weeks following 5/6 nephrectomy (CRF), (b) sham-operated animals, and (c) rats with CRF treated orally with either atorvastatin or arginine in drinking water (modalities which have been shown to enhance eNOS activity and improve endothelial function). Both glomerular and aortic arginine transport were significantly decreased in CRF. Treatment with either arginine or atorvastatin abolished the decrease in arginine uptake in CRF rats. Using reverse transcriptase-polymerase chain reaction and Northern blotting, we found a significant increase in glomerular and aortic CAT-1 mRNA expression in CRF. Western blotting revealed that CAT-1 protein was decreased in CRF, but remained intact following arginine and atorvastatin administration. Renal and systemic arginine uptake is attenuated in CRF, through modulation of CAT-1 protein. These findings provide a possible novel mechanism to eNOS inactivation and endothelial dysfunction in uremia.
Schwartz
I F
IF
Department of Nephrology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Sackler School of Medicine, Israel. dorons@tasmc.health.gov.il
Ayalon
R
R
Chernichovski
T
T
Reshef
R
R
Chernin
G
G
Weinstein
T
T
Litvak
A
A
Levo
Y
Y
Schwartz
D
D
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology; D000069059:Atorvastatin; D001692:Biological Transport; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics*; D027202:Cationic Amino Acid Transporter 2 / Q000235:genetics; D003404:Creatinine / Q000378:metabolism; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014511:Uremia / Q000378:metabolism*
D027201:Cationic Amino Acid Transporter 1; D027202:Cationic Amino Acid Transporter 2; D006538:Heptanoic Acids; D011758:Pyrroles; D009569:Nitric Oxide; D001120:Arginine; D000069059:Atorvastatin; D003404:Creatinine