Blockade of myeloid differentiation protein 2 prevents obesity‐induced inflammation and nephropathy

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 ( MD 2) is an important protein in lipopolysaccharide‐induced innate immunity response and inflammation. We suggested that obesity‐associated renal injury is regulated by MD 2 thereby driving an inflammatory renal injury. The used three mouse models for in vivo study: MD 2 knockout mice ( KO ) maintained on high fat diet ( HFD ), wild‐type mice on HFD plus L6H21, a specific MD 2 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 MAPK s. 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 MD 2 knockout. The in vitro data further confirmed MD 2 mediates PA ‐induced inflammation. MD 2 is causally related with obesity‐associated renal inflammatory injury. We believe that MD 2 is an attractive target for future therapeutic strategies in obesity‐associated kidney diseases.