Advanced Oxidation Protein Products Activate Intrarenal Renin-Angiotensin System via a CD36-mediated, Redox-Dependent Pathway

Antioxid Redox Signal. 2013 Jan 1;18(1):19-35. doi: 10.1089/ars.2012.4603. Epub 2012 Jul 30.

Abstract

Aims: Activation of intrarenal renin-angiotensin system (RAS) has a detrimental effect on the progression of chronic kidney diseases (CKDs), although the regulation of intrarenal RAS remains unclear. The aim of the present study was to evaluate the role of advanced oxidation protein products (AOPPs) in intrarenal RAS activation.

Results: AOPPs upregulated the expression of almost all components of RAS and increased activity of angiotensin-converting enzyme in cultured proximal tubular epithelial cells. The triggering effect of AOPP-albumin was 100-times stronger than that of unmodified albumin. The effect of AOPP-albumin was mainly mediated by a CD36-dependent, redox-sensitive signaling involving activation of protein kinase Cα, NADPH oxidase, and nuclear factor-κB/activation protein-1. Chronic AOPP-albumin loading in unilateral nephrectomy rats resulted in deposition of AOPPs in renal tubular cells accompanied with local RAS activation and functional perturbations such as increase in urinary albumin excretion. Accumulation of AOPPs was also detected in human renal tubular cells and correlated with expression of angiotensin II in renal biopsies from 19 patients with IgA nephropathy.

Innovation and conclusion: This study demonstrated for the first time that AOPPs modified albumin functions as a strong trigger of intrarenal RAS via a CD36-mediated, redox-dependent pathway. Given the fact that accumulation of AOPPs is prevalent in diabetes and CKD, targeting AOPPs could be a strategy for the therapeutic intervention of CKD. Antioxid. Redox Signal. 18, 19-35.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Advanced Oxidation Protein Products / metabolism
  • Advanced Oxidation Protein Products / physiology*
  • Angiotensinogen / genetics
  • Angiotensinogen / metabolism
  • Animals
  • CD36 Antigens / metabolism*
  • Carbazoles / pharmacology
  • Cell Line
  • Epithelial Cells / metabolism
  • Humans
  • Kidney / metabolism
  • Kidney / physiopathology
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice
  • NADPH Oxidases / metabolism
  • NF-kappa B / metabolism
  • Oxidation-Reduction
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Protein Kinase C-alpha / antagonists & inhibitors
  • Protein Kinase C-alpha / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism
  • Renal Insufficiency / metabolism
  • Renin-Angiotensin System*
  • Serum Albumin / metabolism
  • Serum Albumin / physiology*
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism
  • Up-Regulation

Substances

  • Advanced Oxidation Protein Products
  • CD36 Antigens
  • Carbazoles
  • Cd36 protein, rat
  • NF-kappa B
  • Reactive Oxygen Species
  • Receptor, Angiotensin, Type 1
  • Serum Albumin
  • Transcription Factor AP-1
  • Angiotensinogen
  • Go 6976
  • NADPH Oxidases
  • Protein Kinase C-alpha
  • Peptidyl-Dipeptidase A