Differential regulation of Na+ transporters along nephron during ANG II-dependent hypertension: distal stimulation counteracted by proximal inhibition

Am J Physiol Renal Physiol. 2013 Aug 15;305(4):F510-9. doi: 10.1152/ajprenal.00183.2013. Epub 2013 May 29.

Abstract

During angiotensin II (ANG II)-dependent hypertension, ANG II stimulates, while hypertension inhibits, Na(+) transporter activity to balance Na(+) output to input. This study tests the hypothesis that ANG II infusion activates Na(+) transporters in the distal nephron while inhibiting transporters along the proximal nephron. Male Sprague-Dawley rats were infused with ANG II (400 ng·kg(-1)·min(-1)) or vehicle for 2 wk. Kidneys were dissected (cortex vs. medulla) or fixed for immunohistochemistry (IHC). ANG II increased mean arterial pressure by 40 mmHg, urine Na(+) by 1.67-fold, and urine volume by 3-fold, evidence for hypertension and pressure natriuresis. Na(+) transporters' abundance and activation [assessed by phosphorylation (-P) or proteolytic cleavage] were measured by immunoblot. During ANG II infusion Na(+)/H(+) exchanger 3 (NHE3) abundance decreased in both cortex and medulla; Na-K-2Cl cotransporter 2 (NKCC2) decreased in medullary thick ascending loop of Henle (TALH) and increased, along with NKCC2-P, in cortical TALH; Na-Cl cotransporter (NCC) and NCC-P increased in the distal convoluted tubule; and epithelial Na(+) channel subunits and their cleaved forms were increased in both cortex and medulla. Like NKCC2, STE20/SPS1-related proline alanine-rich kinase (SPAK) and SPAK-P were decreased in medulla and increased in cortex. By IHC, during ANG II NHE3 remained localized to proximal tubule microvilli at lower abundance, and the differential regulation of NKCC2 and NKCC2-P in cortex versus medulla was evident. In summary, ANG II infusion increases Na(+) transporter abundance and activation from cortical TALH to medullary collecting duct while the hypertension drives a natriuresis response evident as decreased Na(+) transporter abundance and activation from proximal tubule through medullary TALH.

Keywords: ENaC; NCC; NHE3; NKCC2; SPAK; pressure natriuresis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Blood Pressure / drug effects*
  • Epithelial Sodium Channels / drug effects
  • Epithelial Sodium Channels / metabolism*
  • Hypertension / metabolism*
  • Immunoblotting
  • Immunohistochemistry
  • Kidney / metabolism*
  • Male
  • Membrane Transport Proteins / drug effects
  • Membrane Transport Proteins / metabolism*
  • Nephrons / drug effects
  • Nephrons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium / metabolism*

Substances

  • Epithelial Sodium Channels
  • Membrane Transport Proteins
  • Angiotensin II
  • Sodium