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Am J Pathol. 2015 Aug;185(8):2232-45. doi: 10.1016/j.ajpath.2015.04.016. Epub 2015 Jun 16.

The macrophage phagocytic receptor CD36 promotes fibrogenic pathways on removal of apoptotic cells during chronic kidney injury.

Author information

1
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
2
Seattle Children's Hospital Research Institute, University of Washington, Seattle, Washington.
3
Department of Dentistry, University of Alberta, Edmonton, Alberta, Canada.
4
Seattle Children's Hospital Research Institute, University of Washington, Seattle, Washington. Electronic address: daryl.okamura@seattlechildrens.org.

Abstract

The removal of apoptotic cells is an innate function of tissue macrophages; however, its role in disease progression is unclear. The present study was designed to investigate the role of macrophage CD36, a recognized receptor of apoptotic cells and oxidized lipids, in two models of kidney injury: unilateral ureteral obstruction (UUO) and ischemia reperfusion. To differentiate the macrophage CD36-specific effects in vivo, we generated CD36 chimeric mice by bone marrow transplantation and evaluated the two models. Fibrosis severity was substantially decreased after UUO with a corresponding decrease in matrix synthesis in macrophage CD36-deficient mice. Despite a reduction in fibrosis severity, a 56% increase in apoptotic cells was found without an increase in apoptotic effectors. In addition, a substantial reduction was observed in tumor necrosis factor-α and transforming growth factor-β1 mRNA levels and intracellular bioactive oxidized lipid levels in CD36-deficient macrophages. To validate the functional role of macrophage CD36, we performed unilateral ischemia reperfusion, followed by contralateral nephrectomy. Similarly, we found that the severity of fibrosis was reduced by 55% with a corresponding improvement in kidney function by 88% in macrophage CD36-deficient mice. Taken together, these data suggest that macrophage CD36 is a critical regulator of oxidative fibrogenic signaling and that CD36-mediated phagocytosis of apoptotic cells may serve as an important pathway in the progression of fibrosis.

PMID:
26092500
PMCID:
PMC4530136
DOI:
10.1016/j.ajpath.2015.04.016
[Indexed for MEDLINE]
Free PMC Article

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