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Zinc delays the progression of obesity-related glomerulopathy in mice via down-regulating P38 MAPK-mediated inflammation.

ABSTRACT: OBJECTIVE:Obesity, particularly child obesity, is one of the most common public health problems in the world and raises the risk of end-stage renal disease. Zinc (Zn) is essential for multiple organs in terms of normal structure and function; however, effects of Zn deficiency or supplementation among young individuals with obesity have not been well studied. METHODS:Weaned mice were fed high-fat diets (HFD) with varied contents of Zn (Zn deficient, adequate, and supplemented) for 3 or 6 months. This study examined associations between renal pathogenesis and dietary Zn levels, specifically assessing inflammatory pathways by utilizing P38 MAPK inhibitor SB203580. RESULTS:HFD feeding induced typical syndromes of obesity-related renal disorders, which worsened by Zn marginal deficiency. The progression of obesity-related renal disorders was delayed by Zn supplementation. HFD induced renal inflammation, reflected by increased P38 MAPK phosphorylation along with increases of inflammatory cytokines MCP-1, IL-1?, IL-6, and TNF-?. P38 MAPK inhibition prevented renal pathological changes in mice fed with HFD and HFD/Zn deficiency. CONCLUSIONS:P38 MAPK mediated the renal inflammatory responses, which played a central role in the pathogenesis of HFD-induced renal disorders. Zn could delay the progression of obesity-related kidney disease by down-regulating P38 MAPK-mediated inflammation.

SUBMITTER: Luo M

PROVIDER: S-EPMC7218660 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Zinc delays the progression of obesity-related glomerulopathy in mice via down-regulating P38 MAPK-mediated inflammation.

Luo Manyu M Luo Ping P Zhang Zhiguo Z Payne Kristen K Watson Sara S Wu Hao H Tan Yi Y Ding Yushuang Y Sun Weixia W Yin Xinmin X Zhang Xiang X Liu Gilbert G Wintergerst Kupper K Miao Lining L Cai Lu L

Obesity (Silver Spring, Md.) 20160329 6

<h4>Objective</h4>Obesity, particularly child obesity, is one of the most common public health problems in the world and raises the risk of end-stage renal disease. Zinc (Zn) is essential for multiple organs in terms of normal structure and function; however, effects of Zn deficiency or supplementation among young individuals with obesity have not been well studied.<h4>Methods</h4>Weaned mice were fed high-fat diets (HFD) with varied contents of Zn (Zn deficient, adequate, and supplemented) for ...[more]

PMID: 27028368

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Project description:BackgroundRenal interstitial fibrosis (RIF) is a common pathway to end-stage renal disease regardless of the initial etiology. Currently, the molecular mechanisms for RIF remains not fully elucidated. Nuclear receptor subfamily 4 group A member 1(Nr4a1), a member of the NR4A subfamily of nuclear receptors, is a ligand-activated transcription factor. The role of Nr4a1 in RIF remains largely unknown.MethodsIn this study, we determined the role and action mechanism of Nr4a1 in RIF. We used unilateral ureteral obstruction (UUO) mice and transforming growth factor (TGF)-β1-treated human renal proximal tubular epithelial cells (HK-2 cells) as in vivo and in vitro models of RIF. A specific Nr4a1 agonist Cytosporone B (Csn-B) was applied to activate Nr4a1 both in vivo and in vitro, and Nr4a1 small interfering RNA was applied in vitro. Renal pathological changes were evaluated by hematoxylin and eosin and Masson staining, and the expression of fibrotic proteins including fibronectin (Fn) and collagen-I (Col-I), and phosphorylated p38 MAPK was measure by immunohistochemical staining and western blot analysis.ResultsThe results showed that Nr4a1 was upregulated in UUO mouse kidneys, and was positively correlated with the degree of interstitial kidney injury and the levels of fibrotic proteins. Csn-B treatment aggravated UUO-induced renal interstitial fibrosis, and induced p38 MAPK phosphorylation. In vitro, TGF-β induced Nr4a1 expression, and Nr4a1 downregulation prevented TGF-β1-induced expression of Fn and Col-I and the activation of p38 MAPK. Csn-B induced fibrotic proteins expression and p38 MAPK phosphorylation, and moreover Csn-B induced fibrotic proteins expression was abrogated by treatment with p38 MAPK inhibitor SB203580. We provided further evidence that Csn-B treatment promoted cytoplasmic accumulation of Nr4a1.ConclusionThe findings in the present study indicate that Nr4a1 promotes renal fibrosis potentially through activating p38 MAPK kinase.

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Zinc delays the progression of obesity-related glomerulopathy in mice via down-regulating P38 MAPK-mediated inflammation.

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Zinc delays the progression of obesity-related glomerulopathy in mice via down-regulating P38 MAPK-mediated inflammation.

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