Profound Decrease in Glomerular Arginine Transport by CAT (Cationic Amino Acid Transporter)-1 Contributes to the FLT-1 (FMS-Like Tyrosine Kinase 1) Induced Preeclampsia in the Pregnant Mice. Issue 4 (April 2019)

• Record Type: Journal Article
• Authors: Shashar, Moshe; Zubkov, Asia; Chernichovski, Tamara; Hershkovitz, Rami; Hoffman, Elinoar; Grupper, Ayelet; Weinstein, Talia; Schwartz, Idit F.
• Is Part Of: Hypertension. Volume 73:Issue 4(2019)
• Publication Date: 2019-04
• Subjects: arginine -- nitric oxide -- preeclampsia -- pregnancy -- proteinuria; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.118.12372
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : Endothelial dysfunction because of nitric oxide inactivation has been suggested to play a role in the pathogenesis of preeclampsia. During pregnancy, L-arginine transport by CAT-1 (cationic amino acid transporter 1), the only transporter for eNOS (endothelial nitric oxide synthase) is inhibited. We hypothesize that maternal arginine deficiency contributes to the development of preeclampsia. Adenovirus-mediated overexpression of sFlt-1 (soluble fms-like tyrosine kinase 1) in virgin and pregnant mice resulted in glomerular endotheliosis, hypertension, and albuminuria. L-arginine prevented the increase in blood pressure and albuminuria in Flt-1 pregnant but not in Flt-1 virgin mice. Flt-1 augmented arginine transport in pregnant but not in virgin dames. Ex vivo inhibition of CAT-2 leaving exclusively CAT-1 activity, decreased arginine transport velocities in Flt-1 animals more prominently in pregnant dames. Phosphorylated CAT-1/CAT-1 increased in pregnant, sFlt-1-pregnant, and sFlt-1 virgin mice. CAT-2 increased in Flt-1-pregnant and Flt-1-virgin dames. L-arginine augmented arginine transport in pregnant and Flt-pregnant mice and prevented the increase in pCAT-1 and CAT-2 expression. Glomerular cGMP (cyclic guanosine monophosphate) generation as a measure of eNOS activity was decreased in all Flt-1 treated animals. L-arginine abolished the decrease in cGMP levels only in Flt-1-pregnant mice. In conclusion, glomerular endothelial NO generation is compromised in Flt-1-pregnant mice because of CAT-1 inhibition induced by a combined effect of pregnancy and preeclampsia which involves: phosphorylation of CAT-1 and induction of CAT-2. These processes contribute to the clinical syndrome of preeclampsia in mice and are prevented by L-arginine. Abstract : Supplemental Digital Content is available in the text.