Vascular control of kidney epithelial transporter

Matthew A. Sparks, Emre Dilmen, Donna L. Ralph, Fitra Rianto, Thien A. Hoang, Alison Hollis, Edward J. Diaz, Rishav Adhikari, Gabriel Chew, Enrico G. Petretto, Susan B. Gurley, Alicia A. McDonough, Thomas M. Coffman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT1) receptors in the kidney, stimulating Na+ reabsorption. AT1 receptors in tubular epithelia control expression and stimulation of Na+ transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT1 receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na+ excretion in SMKO mice, we considered whether alterations in Na+ transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na+ transporters and associated proteins. Here, we show that levels of Na+-K+-2Cl- cotransporter isoform 2 (NKCC2) and Na+/H+ exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser71), and phosphorylated NKCC2, along with the cleaved, activated forms of the a- and c-epithelial Na+ channel. However, the increases in a- and c-epithelial Na+ channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na+ excretion observed after cell-specific deletion of AT1 receptors from smooth muscle cells is associated with altered Na+ transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na+ transporters and contributing to the regulation of pressure natriuresis.

Original languageEnglish (US)
Pages (from-to)F1080-F1092
JournalAmerican Journal of Physiology - Renal Physiology
Volume320
Issue number6
DOIs
StatePublished - Jun 2021

Keywords

  • Amiloride
  • Angiotensin
  • Epithelial Na+ channel
  • Furosemide
  • Hypertension

ASJC Scopus subject areas

  • Physiology
  • Urology

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