RRC ID 49247
Author Fang Q, Wang L, Yang D, Chen X, Shan X, Zhang Y, Lum H, Wang J, Zhong P, Liang G, Wang Y.
Title Blockade of myeloid differentiation protein 2 prevents obesity-induced inflammation and nephropathy.
Journal J. Cell. Mol. Med.
Abstract Obesity is a major and independent risk factor of kidney diseases. The pathogenic mechanisms of obesity-associated renal injury are recognized to at least involve a lipid-rich and pro-inflammatory state of the renal tissues, but specific mechanisms establishing causal relation remain unknown. Saturated fatty acids are elevated in obesity, and known to induce chronic inflammation in kidneys. Myeloid differentiation protein 2 (MD2) is an important protein in lipopolysaccharide-induced innate immunity response and inflammation. We suggested that obesity-associated renal injury is regulated by MD2 thereby driving an inflammatory renal injury. The used three mouse models for in vivo study: MD2 knockout mice (KO) maintained on high fat diet (HFD), wild-type mice on HFD plus L6H21, a specific MD2 inhibitor and KO mice given palmitic acid (PA) by IV injection. The in vitro studies were carried out in cultured renal tubular epithelial cells, mouse mesangial cells and primary macrophages, respectively. The HFD mice presented with increased hyperlipidemia, serum creatinine and proteinuria. Renal tissue from HFD mice had increased fibrosis, inflammatory cytokines, macrophage infiltration, and activation of NF-κB and MAPKs. This HFD-induced renal injury profile was not observed in KO mice or L6H21-treated mice. Mice given PA mimmicked the HFD-induced renal injury profiles, which were prevented by MD2 knockout. The in vitro data further confirmed MD2 mediates PA-induced inflammation. MD2 is causally related with obesity-associated renal inflammatory injury. We believe that MD2 is an attractive target for future therapeutic strategies in obesity-associated kidney diseases.
Volume 21(12)
Pages 3776-3786
Published 2017-12
DOI 10.1111/jcmm.13287
PMID 28767204
PMC PMC5706499
MeSH Animals Anti-Inflammatory Agents / pharmacology* Chalcones / pharmacology* Diet, High-Fat / adverse effects* Epithelial Cells / drug effects Epithelial Cells / metabolism Epithelial Cells / pathology Gene Expression Regulation Hyperlipidemias / etiology Hyperlipidemias / genetics Hyperlipidemias / pathology Hyperlipidemias / prevention & control* Kidney / drug effects Kidney / metabolism Kidney / pathology Lymphocyte Antigen 96 / antagonists & inhibitors Lymphocyte Antigen 96 / deficiency Lymphocyte Antigen 96 / genetics* Macrophages / drug effects Macrophages / metabolism Macrophages / pathology Male Mesangial Cells / drug effects Mesangial Cells / metabolism Mesangial Cells / pathology Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases / genetics Mitogen-Activated Protein Kinases / metabolism NF-kappa B / genetics NF-kappa B / metabolism Nephritis / etiology Nephritis / genetics Nephritis / pathology Nephritis / prevention & control* Obesity / drug therapy* Obesity / etiology Obesity / genetics Obesity / pathology Primary Cell Culture Signal Transduction
IF 4.302
Resource
Mice B6.129P2-Ly96<tm1Kmiy>(RBRC02388)