Lysophosphatidic acid (LPA) as a modulator of plasma membrane Ca2+-ATPase from basolateral membranes of kidney proximal tubules

J Physiol Biochem. 2021 May;77(2):321-329. doi: 10.1007/s13105-021-00800-5. Epub 2021 Mar 11.

Abstract

Lysophosphatidic acid (LPA) acts through the activation of G protein-coupled receptors, in a Ca2+-dependent manner. We show the effects of LPA on the plasma membrane Ca2+-ATPase (PMCA) from kidney proximal tubule cells. The Ca2+-ATPase activity was inhibited by nanomolar concentrations of LPA, with maximal inhibition (~50%) obtained with 20 nM LPA. This inhibitory action on PMCA activity was blocked by Ki16425, an antagonist for LPA receptors, indicating that this lipid acts via LPA1 and/or LPA3 receptor. This effect is PKC-dependent, since it is abolished by calphostin C and U73122, PKC, and PLC inhibitors, respectively. Furthermore, the addition of 10-8 M PMA, a well-known PKC activator, mimicked PMCA modulation by LPA. We also demonstrated that the PKC activation leads to an increase in PMCA phosphorylation. These results indicate that LPA triggers LPA1 and/or LPA3 receptors at the BLM, inducing PKC-dependent phosphorylation with further inhibition of PMCA. Thus, LPA is part of the regulatory lipid network present at the BLM and plays an important role in the regulation of intracellular Ca2+ concentration that may result in significant physiological alterations in other Ca2+-dependent events ascribed to the renal tissue.

Keywords: Bioactive lipids; Calcium; Kidney; Lysophosphatidic acid; PKC; Renal physiology.

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cell Fractionation
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Estrenes / pharmacology
  • Gene Expression Regulation
  • Ion Transport / drug effects
  • Isoxazoles / pharmacology
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Lysophospholipids / pharmacology*
  • Naphthalenes / pharmacology
  • Phosphorylation / drug effects
  • Plasma Membrane Calcium-Transporting ATPases / antagonists & inhibitors
  • Plasma Membrane Calcium-Transporting ATPases / genetics*
  • Plasma Membrane Calcium-Transporting ATPases / metabolism
  • Primary Cell Culture
  • Propionates / pharmacology
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Pyrrolidinones / pharmacology
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors
  • Receptors, Lysophosphatidic Acid / genetics*
  • Receptors, Lysophosphatidic Acid / metabolism
  • Signal Transduction
  • Swine
  • Tetradecanoylphorbol Acetate / pharmacology
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / genetics
  • Type C Phospholipases / metabolism

Substances

  • 3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
  • Estrenes
  • Isoxazoles
  • Lysophospholipids
  • Naphthalenes
  • Propionates
  • Protein Isoforms
  • Pyrrolidinones
  • Receptors, Lysophosphatidic Acid
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Protein Kinase C
  • Type C Phospholipases
  • Plasma Membrane Calcium-Transporting ATPases
  • calphostin C
  • Tetradecanoylphorbol Acetate
  • lysophosphatidic acid
  • Calcium