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Megalin/LRP2 expression is induced by peroxisome proliferator-activated receptor -alpha and -gamma: implications for

Felipe Cabezas1, Jonathan Lagos, Carlos Céspedes

  • 1Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Plos One
|February 12, 2011
PubMed
Abstract

Insights

Peroxisome proliferator-activated receptors (PPARs) positively regulate megalin expression, a key endocytic receptor in the kidney. This finding offers potential therapeutic strategies for kidney diseases where megalin function is impaired.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Renal Physiology

Background:

  • Megalin is a crucial endocytic receptor in kidney proximal tubule cells (PTCs), vital for development and adult physiology.
  • Megalin internalizes various molecules, including apolipoproteins, vitamins, and hormones, via carrier proteins.
  • Regulation of megalin expression remains largely unknown despite its significant roles.

Purpose of the Study:

  • To investigate whether peroxisome proliferator-activated receptors (PPARs) regulate megalin expression.
  • To identify response elements for PPARs within the human megalin promoter.

Main Methods:

  • Analysis of the human megalin promoter for PPAR response elements.
  • Treatment of epithelial cell lines and mouse kidneys with PPAR ligands and antagonists.
  • Electrophoretic Mobility Shift Assay (EMSA) to confirm PPAR binding to the promoter.
  • Luciferase reporter assays to assess promoter activity.
  • In vitro studies using bovine serum albumin (BSA) to mimic kidney damage.
  • In vivo studies in rats with BSA-induced kidney injury.

Main Results:

  • PPARα and PPARγ ligands significantly increased megalin mRNA and protein expression in epithelial cells.
  • PPAR binding to response elements in the megalin promoter was confirmed.
  • PPAR activation enhanced megalin expression in mouse kidneys.
  • PPAR agonists protected against BSA-induced reduction of megalin expression in PTCs.
  • PPARγ agonist treatment counteracted BSA-induced megalin downregulation and proteinuria in rats.

Conclusions:

  • PPARα and PPARγ agonists positively regulate megalin expression.
  • This regulatory mechanism is significant for physiological processes mediated by megalin.
  • Understanding this regulation could impact treatments for kidney diseases like diabetic nephropathy and hypertensive nephropathy, where megalin expression is often compromised.

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