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.

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BackgroundAlthough the peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone has significant anti-inflammatory properties, no scientific studies have provided new insights in its pharmacological properties with respect to acute respiratory distress syndrome (ARDS). The present investigation aimed to evaluate whether rosiglitazone can reduce apoptosis and inflammation in a lipopolysaccharide (LPS)-induced acute respiratory distress syndrome in vitro model.Material/MethodsHuman umbilical vein endothelial cells (HUVECs) were treated with 1 μg/ml LPS in the absence or presence of 10 μM rosiglitazone for 24 h. Cell viability was measured by MTT assay. Flow cytometry was used to examine the cell apoptosis and ROS production in HUVECs response to LPS and rosiglitazone. The levels of pro-inflammatory cytokine factors, including TNF-α, IL-6, CXCL12, and CXCR4, were measured by ELISA, real-time PCR, and Western blot assay, respectively. The expression of PPARγ, Bcl-2, and Bax and the activity of JAK2 and STAT3 were also investigated by Western blot assay.ResultsWe found that rosiglitazone significantly inhibited LPS-induced cell apoptosis, ROS production, and inflammation in HUVECs. Furthermore, we found a significant reduction of JAK2/STAT3 activation and the Bax/Bcl-2 ratio in LPS-induced HUVECs response to rosiglitazone treatment.ConclusionsTreatment with rosiglitazone can reduce apoptosis and inflammation in HUVECs induced by LPS.

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