Blockade of myeloid differentiation protein 2 prevents obesity-induced inflammation and nephropathy
Qilu Fang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
These authors contributed equally to this work.Search for more papers by this authorLintao Wang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
These authors contributed equally to this work.Search for more papers by this authorDaona Yang
Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorXiong Chen
Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorXiaoou Shan
Department of Pediatrics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 China
Search for more papers by this authorYali Zhang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorHazel Lum
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorJingying Wang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorPeng Zhong
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorCorresponding Author
Guang Liang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Correspondence to: Guang LIANG, Ph.D.
E-mail: [email protected]
Yi WANG, Ph.D.
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Yi Wang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Correspondence to: Guang LIANG, Ph.D.
E-mail: [email protected]
Yi WANG, Ph.D.
E-mail: [email protected]
Search for more papers by this authorQilu Fang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
These authors contributed equally to this work.Search for more papers by this authorLintao Wang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
These authors contributed equally to this work.Search for more papers by this authorDaona Yang
Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorXiong Chen
Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorXiaoou Shan
Department of Pediatrics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 China
Search for more papers by this authorYali Zhang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorHazel Lum
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorJingying Wang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorPeng Zhong
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Search for more papers by this authorCorresponding Author
Guang Liang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Correspondence to: Guang LIANG, Ph.D.
E-mail: [email protected]
Yi WANG, Ph.D.
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Yi Wang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Correspondence to: Guang LIANG, Ph.D.
E-mail: [email protected]
Yi WANG, Ph.D.
E-mail: [email protected]
Search for more papers by this authorAbstract
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.
Supporting Information
| Filename | Description |
|---|---|
| jcmm13287-sup-0001-SupInfo.docWord document, 3.7 MB |
Data S1 Materials and methods. Figure S1 MD2 expression and activation in the kidney tissues of high fat diet (HFD)-fed mices Figure S2 MD2 knockout affects serum TG, but not LDL and TCH, in HFD-fed mice. Figure S3 The quantitative data for the staining images in Figure 1G. Figure S4 Upper panel: an amplified image (400X) for TNF-α staining in Figure 2J. Figure S5 MD2 expression and activation in the kidney tissues of mice with 2-month HFD feeding. Figure S6 Administration with MD2 inhibitor L6H21 did not affect serum lipid profile in HFD-fed mice. Figure S7 The quantitative data for the staining images in Figure 3D. Figure S8 MD2 inhibition by L6H21 prevents macrophage infiltration in HFD kidney. Figure S9 MD2 inhibition by L6H21 prevents high fat diet-induced MCP-1 expression in mouse kidney. Figure S10 HFD increases FFA levels in mouse kidney tissues. Figure S11 Palmitic acid injection increases kidney weight in mice. Figure S12 The quantitative data for the staining images in Figure 4C. Figure S13 Palmitic acid induces MD2-dependent renal tissue fibrosis and inflammation in vivo. Figure S14 The quantitative data for the staining images in Figure S6H Figure S15 PA activates MD2-dependent inflammatory activity in renal mesangial cells. Table S1 Primers used for real-time qPCR assay. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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