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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.
Hypertension 2019; 73(4):878-884H

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.

Authors+Show Affiliations

From the Departments of Nephrology (M.S., T.C., E.H., A.G., T.W., I.F.S.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel.Pathology (A.Z.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel.From the Departments of Nephrology (M.S., T.C., E.H., A.G., T.W., I.F.S.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel.Internal Medicine "T" (R.H., I.F.S.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel.From the Departments of Nephrology (M.S., T.C., E.H., A.G., T.W., I.F.S.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel.From the Departments of Nephrology (M.S., T.C., E.H., A.G., T.W., I.F.S.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel.From the Departments of Nephrology (M.S., T.C., E.H., A.G., T.W., I.F.S.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel.From the Departments of Nephrology (M.S., T.C., E.H., A.G., T.W., I.F.S.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel. Internal Medicine "T" (R.H., I.F.S.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Israel.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30798662

Citation

Shashar, Moshe, et al. "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." Hypertension (Dallas, Tex. : 1979), vol. 73, no. 4, 2019, pp. 878-884.
Shashar M, Zubkov A, Chernichovski T, et al. 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. Hypertension. 2019;73(4):878-884.
Shashar, M., Zubkov, A., Chernichovski, T., Hershkovitz, R., Hoffman, E., Grupper, A., ... Schwartz, I. F. (2019). 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. Hypertension (Dallas, Tex. : 1979), 73(4), pp. 878-884. doi:10.1161/HYPERTENSIONAHA.118.12372.
Shashar M, et al. 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. Hypertension. 2019;73(4):878-884. PubMed PMID: 30798662.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Shashar,Moshe, AU - Zubkov,Asia, AU - Chernichovski,Tamara, AU - Hershkovitz,Rami, AU - Hoffman,Elinoar, AU - Grupper,Ayelet, AU - Weinstein,Talia, AU - Schwartz,Idit F, PY - 2019/2/26/pubmed PY - 2019/2/26/medline PY - 2019/2/26/entrez KW - arginine KW - nitric oxide KW - preeclampsia KW - pregnancy KW - proteinuria SP - 878 EP - 884 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 73 IS - 4 N2 - 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. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/30798662/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 L2 - http://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.118.12372?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -