title: Attenuated glomerular arginine transport prevents hyperfiltration and induces HIF-1α in the pregnant uremic rat.
abstract: Pregnancy worsens renal function in females with chronic renal failure (CRF) through an unknown mechanism. Reduced nitric oxide (NO) generation induces renal injury. Arginine transport by cationic amino acid transporter-1 (CAT-1), which governs endothelial NO generation, is reduced in both renal failure and pregnancy. We hypothesize that attenuated maternal glomerular arginine transport promotes renal damage in CRF pregnant rats. In uremic rats, pregnancy induced a significant decrease in glomerular arginine transport and cGMP generation (a measure of NO production) compared with CRF or pregnancy alone and these effects were prevented by l-arginine. While CAT-1 abundance was unchanged in all experimental groups, protein kinase C (PKC)-α, phosphorylated PKC-α (CAT-1 inhibitor), and phosphorylated CAT-1 were significantly augmented in CRF, pregnant, and pregnant CRF animals; phenomena that were prevented by coadministrating l-arginine. α-Tocopherol (PKC inhibitor) significantly increased arginine transport in both pregnant and CRF pregnant rats, effects that were attenuated by ex vivo incubation of glomeruli with PMA (a PKC stimulant). Renal histology revealed no differences between all experimental groups. Inulin and p-aminohippurate clearances failed to augment and renal cortical expression of hypoxia inducible factor-1α (HIF-1α) significantly increased in CRF pregnant rat, findings that were prevented by arginine. These studies suggest that in CRF rats, pregnancy induces a profound decrease in glomerular arginine transport, through posttranslational regulation of CAT-1 by PKC-α, resulting in attenuated NO generation. These events provoke renal damage manifested by upregulation of renal HIF-1α and loss of the ability to increase glomerular filtration rate during gestation.
authors.affiliation: Department of Nephrology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel.
authors.forename: Idit F
authors.initials: IF
authors.lastname: Schwartz
authors.forename: Ayelet
authors.initials: A
authors.lastname: Grupper
authors.forename: Hila
authors.initials: H
authors.lastname: Soetendorp
authors.forename: Oren
authors.initials: O
authors.lastname: Hillel
authors.forename: Ido
authors.initials: I
authors.lastname: Laron
authors.forename: Tamara
authors.initials: T
authors.lastname: Chernichovski
authors.forename: Merav
authors.initials: M
authors.lastname: Ingbir
authors.forename: Allexander
authors.initials: A
authors.lastname: Shtabski
authors.forename: Talia
authors.initials: T
authors.lastname: Weinstein
authors.forename: Gil
authors.initials: G
authors.lastname: Chernin
authors.forename: Moshe
authors.initials: M
authors.lastname: Shashar
authors.forename: Rami
authors.initials: R
authors.lastname: Hershkoviz
authors.forename: Doron
authors.initials: D
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001693:Biological Transport, Active; D015153:Blotting, Western; D027201:Cationic Amino Acid Transporter 1 / Q000096:biosynthesis; D002851:Chromatography, High Pressure Liquid; D006152:Cyclic GMP / Q000096:biosynthesis; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D047468:Immunoprecipitation; D007444:Inulin / Q000652:urine; D007678:Kidney Glomerulus / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000502:physiology; D014511:Uremia / Q000378:metabolism*; D014810:Vitamin E / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000652:urine
chemical_list: D027201:Cationic Amino Acid Transporter 1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014810:Vitamin E; D007444:Inulin; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D051571:Protein Kinase C-alpha; D006152:Cyclic GMP; D010130:p-Aminohippuric Acid