Hyperlipidemia, an important risk factor for cardiovascular and end-stage renal diseases, often aggravates renal injury and compromises kidney function. Here, histological analysis of human kidney samples revealed that high
lipid levels induced the development of renal
fibrosis. To elucidate the mechanism underlying
lipid nephrotoxicity, we used two types of mouse models (
Apoe-/- and C57BL/6 mice fed a 45 and 60% high-fat diet, respectively). Histological analysis of kidney tissues revealed high-
lipid-induced renal
fibrosis and
inflammation; this was confirmed by examining fibrotic and inflammatory marker expression using Western blotting and real-time polymerase chain reaction.
Oxidized low-density lipoprotein (
OX-LDL) significantly induced the fibrotic response in HK-2 tubular epithelial cells.
RNA-sequencing and Gene Ontology analysis of differentially expressed mRNAs in
OX-LDL-treated HK-2 tubular epithelial cells and real-time PCR validation in
Apoe-/- mice showed that the expression of thrombospondin-1 (THBS1) in the high-fat group was significantly higher than that of the other top known genes, along with significant overexpression of its receptor CD47. THBS1 knockdown cells verified its relation to
OX-LDL-induced
fibrosis and
inflammation. Liquid chromatography tandem mass spectrometry and STRING functional
protein association network analyses predicted that THBS1/CD47 modulated the interaction between γ-
catenin and
E-cadherin and was involved in epithelial-mesenchymal transition, which was supported by immunoprecipitation and immunohistochemistry. CD47 downregulation following transfection with
small-hairpin RNA in
OX-LDL-treated tubular epithelial cells and treatment with anti-CD47 antibody restored the expression of
E-cadherin and attenuated renal injury,
fibrosis, and inflammatory response in
OX-LDL-treated cells and in
type 2 diabetes mellitus. These findings indicate that CD47 may serve as a potential therapeutic target in long-term
lipid-induced kidney injury.