NYMC Faculty Publications

Regulation of NKCC2B by TNF-α in Response to Salt Restriction

DOI

10.1152/ajprenal.00388.2019

Journal Title

American Journal of Physiology: Renal Physiology

First Page

273

Last Page

282

Document Type

Article

Publication Date

1-1-2020

Department

Pharmacology

Abstract

We previously showed that tumor necrosis factor-alpha (TNF) produced by renal epithelial cells inhibits NKCC2 activity as part of a mechanism that attenuates increases in blood pressure in response to high sodium chloride intake. As the role of TNF in the kidney is still being defined, the effects of low salt intake on TNF and NKCC2B expression were determined. Mice given a low salt (0.02% NaCl) diet (LSD) for 7 days exhibited a 62+/-7.4% decrease in TNF mRNA accumulation in the renal cortex. Mice ingesting LSD also exhibited about a 63% increase in cortical thick ascending limb of Henle's loop (TAL) phospho-NKCC2 (pNKCC2) expression and a concomitant 3- fold increase in NKCC2B mRNA abundance without a concurrent change in NKCC2A mRNA accumulation. NKCC2B mRNA levels increased 5-fold in mice ingesting LSD that also received an intrarenal injection of a lentivirus construct that specifically silenced TNF in the kidney (U6-TNF-ex4) compared with mice injected with control lentivirus. Administration of a single intrarenal injection of murine recombinant TNF (5ng/g body weight) attenuated the increases of NKCC2B mRNA by approximately 50% and inhibited the increase in pNKCC2 by approximately 54% in renal cortex from mice given LSD for 7 days. Renal silencing of TNF decreased urine volume and NaCl excretion in mice given LS, effects that were reversed when NKCC2B was silenced in the kidney. Collectively, these findings demonstrate that downregulation of renal TNF production in response to LS conditions contributes to the regulation of sodium chloride reabsorption via an NKCC2B-dependent mechanism.

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