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

Tue, 2016-08-23 11:13 -- voskuhlt
TitleThe macrophage phagocytic receptor CD36 promotes fibrogenic pathways on removal of apoptotic cells during chronic kidney injury.
Publication TypeJournal Article
Year of Publication2015
AuthorsPennathur S, Pasichnyk K, Bahrami NM, Zeng L, Febbraio M, Yamaguchi I, Okamura DM
JournalAm J Pathol
Volume185
Issue8
Pagination2232-45
Date Published2015 Aug
ISSN1525-2191
KeywordsAnimals, Antigens, CD36, Apoptosis, Fibrosis, Kidney, Macrophage Activation, Macrophages, Male, Mice, Mice, Knockout, Reperfusion Injury, Ureteral Obstruction
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.

DOI10.1016/j.ajpath.2015.04.016
Alternate JournalAm. J. Pathol.
PubMed ID26092500
PubMed Central IDPMC4530136
Grant List5 K08 DK073497 / DK / NIDDK NIH HHS / United States
5 R03 DK083648 / DK / NIDDK NIH HHS / United States
DK081943 / DK / NIDDK NIH HHS / United States
DK082841 / DK / NIDDK NIH HHS / United States
DK89503 / DK / NIDDK NIH HHS / United States
P30 DK017047 / DK / NIDDK NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States