A Study Of Protective Effects And Mechanisms Of Zinc On Obesity-related Glomerulopathy In Mice

Obesity is a common chronic metabolism disease and has been a major health problem all around the world. According to the reports form World Health Oganization on 2014, the obese population all around the world has doubled to 13% since 1980 s, which are over 600 millon. The morbidity of obesity is correlative with socioeconomic status and is more common in developed regions. More than 33% of the adults and about 17% youth in USA are obese. However, with the increasement of Chinese people’s life quality, the morbidity in China increase rapidly. In some economic developed costal areas, the obese people even reach to 30-40% of local population. Obesity is often combined with increased inflammation levels, insulin resistance and hyperlipaemia, which can cause diabetes, cardiovascular disease, stoke and some kinds of cancer. Obesity is an independent dangerous factor that cause kidney damage. Severe obesity increased renal blood flow and increased glomerular filtration rate and caused increased albumin extraction rate. The kidney damage caused by obesity is named obesity-related glomerulopathy(ORG). The typical symptom of ORG is albumin uria. ORG develops progressively and finally cause loss of kidney function. With the increasing incidence rate of obesity in recent years, ORG is treated with more attentions. While the mechanism of ORG remains unclear, treatments of ORG are maily about etiological treatment.As an essencial trace element of humans, Zinc has lots of important function during growth and development. Zinc is necessary in development of brain and intelligence and maintain the functionof lymphocyte. Lack of Zinc can cause slowing growth, developmental disabilities and decrease of immunity, which can cause various kinds of diseases such as anorexia, skin rough and slow recovery and decrease in male reproductive functions. Zinc is the core of many ‘Zinc finger’ protein and is very important in maintain the structures and functions. Zinc is also the activator of various kinds of transfactors and has significant biofunctions. Maintaince of insulin protein structure also needs Zinc. Zinc has the biological functions of anti-inflammation, anti-oxidative stress and increasing the sensitivity of insulin. Zinc deficiency is common under obesity, diabetes and aged conditions. Studies showed that no matter in animal models or patients under obese or diabete conditions, Zinc supplement dcreased the inflammation and oxidative stress levels and increased insulin sensivity, demonstrated that Zinc supplementation is benifical. However, researches about the effects of Zinc in ORG individuals are rarely reported.To discover the role of Zinc in ORG and define the machanisms, we set up obese mice model caused by different reasons and treat them with different Zinc intake levels. We first choose C57BL/6J mice and feed them with high-fat-diet(HFD) to set up the diet-induced obesity model. We also add three different levels of Zinc into the diet to mimic the condition of Zinc deficiency, normal Zinc and Zinc supplement and then observe the effects of different levels of Zinc intake on obese kidney. We find the HFD induced typical symptoms of obesity such as increased bodyweight, dyslipidemia and insulin disorders with ORG syptoms like protein uria and kidney enlargement. ORG is worsened in Zinc deficiency conditions while Zinc supplement could protect kidney in eraly time points and delay the progression of ORG. HFD increases the inflammation levels in kidney characterized by significantly increased inflammation associated P38 MAPK and NF-κB pathways and inflammatory cytokines like TNF-α and IL-6. To further define the effects of Zinc on these pathways, after receiving the treatment of P38 MAPK specific inhibitor SB203580, the expressions of P38 MAPK and its downstream inflammtiory cytokines in mice kidney are inhibited and kidney damage is prevented. After treating the kidney intrinsic cells with fatty acid in vitro, the P38 MAPK pathay and inflammation markers are up-regulated. Zinc deficiency contributes to the activation of P38 MAPK pathway and worsen the inflammation. SB203580 and Zinc supplement could inhibit P38 MAPK pathway and downstream inflammation response. In long-term ORG models, we further find the relationship between Zinc and A20, a Zinc finger protein, which is down-regulating under Zinc deficiency conditions that indirectly decreased the inhibiton effects of NF-κB pathway and clearfy the mechanisms of Zinc on NF-κB pathway. We also choose B6.BKS(D)-Leprdb/J transgenetic obese mice to set up the gene-induced obesity model and feed them with different levels of Zinc diet. Results show that compared with HFD feeding mice, these mice develop sever kidney damage with significant kidney fibrosis and Zinc deficiency contributes to the kidney damage.Above all we are the first to set up the obese and ORG animal models caused by different reasons. We get the conclusion: Zinc plays an important role in the progression of ORG. The mechanism of Zinc in ORG is inhibiting P38 MAPK and NF-κB pathways to inhibit the renal inflammatory respons, then protect the kidney against obesity. Our study suggests that inflammation is the centrol step of the progression of ORG which is mediated by P38 MAPK and NF-κB pathways. Zinc deficiency could contribute to the two pathways and worsen the inflammatory response. Zinc supplement could inhibit P38 MAPK pathway in early time point and delay obesity induced kidney damage. Our study also provides a theory support of Zinc supplement theropy in clinic.