Faculty Collaboration Database

NOX4/H₂O₂/mTORC1 Pathway in Salt-Induced Hypertension and Kidney Injury. Hypertension 2020 Jul;76(1):133-143

Date

06/02/2020

Pubmed ID

32475313

Pubmed Central ID

PMC10629473

DOI

10.1161/HYPERTENSIONAHA.120.15058

Scopus ID

2-s2.0-85086346307 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

We have reported that a high-salt (4.0% NaCl) dietary intake activates mTORC1 and inhibition of this pathway with rapamycin blunts the chronic phase of salt-induced hypertension and renal injury in Dahl salt-sensitive (SS) rats. In SS rats, high-salt intake is known to increase the renal production of H₂O₂ by NOX4, the most abundant NOX isoform in the kidney, and the global knockout of NOX4 blunts salt-sensitivity in these rats. Here, we explored the hypothesis that elevations of H₂O₂ by NOX4 in high-salt fed SS rat stimulate mTORC1 for the full development of salt-induced hypertension and renal injury. Our in vitro studies found that H₂O₂ activates mTORC1 independent of PI3K/AKT and AMPK pathways. To determine the in vivo relevance of NOX4/H₂O₂/mTORC1 in the salt-induced hypertension, SS-Nox4 knockout (SS^Nox4-/-) rats were daily administrated with vehicle/rapamycin fed a high-salt diet for 21 days. Rapamycin treatment of SS^Nox4-/- rats had shown no augmented effect on the salt-induced hypertension nor upon indices of renal injury. Significant reductions of renal T lymphocyte and macrophage together with inhibition of cell proliferation were observed in rapamycin treated rats suggesting a role of mTORC1 independent of NOX4 in the proliferation of immune cell. Given the direct activation of mTORC1 by H₂O₂ and absence of any further protection from salt-induced hypertension in rapamycin-treated SS^Nox4-/- rats, we conclude that NOX4-H₂O₂ is a major upstream activator of mTORC1 that contributes importantly to salt-induced hypertension and renal injury in the SS rat model.

Author List

Kumar V, Kurth T, Zheleznova NN, Yang C, Cowley AW Jr

Author

Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenylate Kinase
Animals
Cell Line
Chromones
Hydrogen Peroxide
Hypertension
Kidney
Kidney Diseases
Male
Mechanistic Target of Rapamycin Complex 1
Morpholines
NADPH Oxidase 4
Phosphatidylinositol 3-Kinases
Phosphorylation
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt
Rats
Rats, Inbred Dahl
Sirolimus
Sodium Chloride, Dietary