(Pro)Renin receptor regulates potassium homeostasis through a local mechanism

Am J Physiol Renal Physiol. 2017 Sep 1;313(3):F641-F656. doi: 10.1152/ajprenal.00043.2016. Epub 2016 Jul 20.

Abstract

(Pro)renin receptor (PRR) is highly expressed in the distal nephron, but it has an unclear functional implication. The present study was conducted to explore a potential role of renal PRR during high K+ (HK) loading. In normal Sprague-Dawley rats, a 1-wk HK intake increased renal expression of full-length PRR and urinary excretion of soluble PRR (sPRR). Administration of PRO20, a decoy peptide antagonist of PRR, in K+-loaded animals elevated plasma K+ level and decreased urinary K+ excretion, accompanied with suppressed urinary aldosterone excretion and intrarenal aldosterone levels. HK downregulated Na+-Cl- cotransporter (NCC) expression but upregulated CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2), renal outer medullary K+ channel (ROMK), calcium-activated potassium channel subunit α1 (α-BK), α-Na+-K+-ATPase (α-NKA), and epithelial Na+ channel subunit β (β-ENaC), all of which were blunted by PRO20. After HK loading was completed, urinary, but not plasma renin, was upregulated, which was blunted by PRO20. The same experiments that were performed using adrenalectomized (ADX) rats yielded similar results. Interestingly, spironolactone treatment in HK-loaded ADX rats attenuated kaliuresis but promoted natriuresis, which was associated with the suppressed responses of β-ENaC, α-NKA, ROMK, and α-BK protein expression. Taken together, we discovered a novel role of renal PRR in regulation of K+ homeostasis through a local mechanism involving intrarenal renin-angiotensin-aldosterone system and coordinated regulation of membrane Na+- and K+-transporting proteins.

Keywords: (Pro)renin receptor; CYP11B2; Na+-Cl− cotransporter; aldosterone; kidney; potassium.

MeSH terms

  • Adrenalectomy
  • Aldosterone / metabolism
  • Animals
  • Cytochrome P-450 CYP11B2 / metabolism
  • Disease Models, Animal
  • Epithelial Sodium Channels / metabolism
  • Homeostasis
  • Hyperkalemia / blood
  • Hyperkalemia / genetics
  • Hyperkalemia / metabolism*
  • Hyperkalemia / urine
  • Kidney / drug effects
  • Kidney / metabolism*
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism
  • Male
  • Mineralocorticoid Receptor Antagonists / pharmacology
  • Peptide Fragments / pharmacology
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Potassium, Dietary*
  • Proton-Translocating ATPases / antagonists & inhibitors
  • Proton-Translocating ATPases / genetics
  • Proton-Translocating ATPases / metabolism*
  • Rats, Sprague-Dawley
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Renin / pharmacology
  • Renin-Angiotensin System* / drug effects
  • Signal Transduction
  • Solute Carrier Family 12, Member 3 / metabolism
  • Spironolactone / pharmacology
  • Vacuolar Proton-Translocating ATPases

Substances

  • Epithelial Sodium Channels
  • Kcnj1 protein, rat
  • Kcnma1 protein, rat
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Mineralocorticoid Receptor Antagonists
  • PRO20 peptide
  • Peptide Fragments
  • Potassium Channels, Inwardly Rectifying
  • Potassium, Dietary
  • Receptors, Cell Surface
  • Scnn1b protein, rat
  • Slc12a3 protein, rat
  • Solute Carrier Family 12, Member 3
  • Spironolactone
  • Aldosterone
  • Cytochrome P-450 CYP11B2
  • Renin
  • ATP6AP2 protein, rat
  • Vacuolar Proton-Translocating ATPases
  • Proton-Translocating ATPases