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CD36 and Na/K-ATPase-α1 form a proinflammatory signaling loop in kidney

David J Kennedy1, Yiliang Chen, Wenxin Huang

  • 1Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Hypertension (Dallas, Tex. : 1979)
|November 23, 2012
PubMed

Insights

Diet-induced hyperlipidemia promotes kidney inflammation and fibrosis by activating scavenger receptor CD36 and the Na/K-ATPase in kidney cells and macrophages. Blocking CD36 improves kidney function in mice.

Area of Science:

  • Nephrology
  • Cardiovascular Biology
  • Immunology

Background:

  • Proatherogenic, hyperlipidemic states elevate ligands for scavenger receptor CD36 (e.g., oxidized low-density lipoprotein [oxLDL]) and Na/K-ATPase (e.g., cardiotonic steroids).
  • These factors exacerbate inflammation, oxidative stress, and chronic kidney disease (CKD) progression.
  • A potential CD36/Na/K-ATPase inflammatory loop between proximal tubule cells (PTCs) and macrophages in CKD is poorly understood.

Purpose of the Study:

  • To investigate the role of a CD36/Na/K-ATPase-dependent inflammatory paracrine loop between PTCs and macrophages in diet-induced obesity and hyperlipidemia.
  • To determine if inhibiting this loop ameliorates renal inflammation and fibrosis.

Main Methods:

  • ApoE(-/-) and apoE(-/-)/cd36(-/-) mice were fed a high-fat diet for up to 32 weeks.
  • Physiological and histological changes in renal function were assessed.
  • Coimmunoprecipitation and crosslinking assays examined CD36 and Na/K-ATPase α-1 localization and interaction.
  • Macrophage migration and reactive oxygen species (ROS) production were measured in vitro and in vivo.

Main Results:

  • ApoE(-/-)/cd36(-/-) mice exhibited improved creatinine clearance and blood pressure compared to apoE(-/-) mice.
  • Histology revealed reduced macrophage accumulation, foam cell formation, oxidant stress, and interstitial fibrosis in apoE(-/-)/cd36(-/-) mice.
  • CD36 and Na/K-ATPase α-1 colocalized in PTCs and macrophages, with increased association upon oxLDL or ouabain treatment.
  • Oxidized LDL and ouabain stimulated PTCs, increasing macrophage migration and ROS production.

Conclusions:

  • Ligands in hyperlipidemic states activate CD36 and Na/K-ATPase, initiating an inflammatory loop between PTCs and macrophages.
  • This loop drives chronic inflammation, oxidative stress, and fibrosis, contributing to renal dysfunction in hyperlipidemic conditions.
  • Targeting CD36 may offer a therapeutic strategy for managing kidney disease associated with hyperlipidemia.

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