Chitosan Oligosaccharide Ameliorates Kidney Injury by Improving Intestinal Barrier Dysfunction and Lipid Metabolism in Obese-insulin Resistant Rats

Abstract

INTRODUCTION: Obesity remains a global health problem. High-fat diet (HFD) consumption increases the risk of type 2 diabetes and initiates kidney injury. Chitosan Oligosaccharide (COS) provides anti-obesity effects through several mechanisms. However, the effects of COS on preventing obesity-related kidney injury in obese-insulin resistance have not been studied. A novel action of COS in activating intestinal tight junction assembly was reported in in vitro via calcium sensing receptor-mediated AMP-activated protein kinase (CaSR/AMPK) activation. HFD-induced gut dysbiosis is related with intestinal barrier dysfunction and systemic low-grade inflammation. Therefore, AMPK activation might be a therapeutic target for preventing obesity-related complications. Here, we explored the protective effects of COS in obesity-induced kidney dysfunction and the involved molecular mechanisms. We hypothesized that COS might exert renoprotection against obesity-induced kidney injury through increasing intestinal barrier integrity and lipid excretion. METHODS: Male Wistar rats were fed with HFD for 16 weeks to induce obesity. Next, HFD rats were randomly divided into 4 groups: HFD, HFD treated with COS 5 or 10 mg/kg/day (COS5 or COS10) and HFD treated with metformin 30 mg/kg/day (MET). The interventions were orally treated for 8 weeks. At the end of experiment, blood, feces, intestinal and renal tissue samples were collected for further investigations. RESULTS: After 16 weeks of high-fat diet feeding, obesity and glucose intolerance were presented in HFD compared to normal diet (ND) rats, as indicated by the significant increases in body weight (BW), plasma cholesterol and total area under the curve for glucose (TAUCg). Kidney injury were observed at week 24, as shown by elevated kidney injury score and serum creatinine. Treatment with COS5 or COS10 significantly decreased BW, hypercholesterolemia, glucose intolerance and kidney dysfunction. Interestingly, COS10 markedly increased fecal lipid excretion compared with HFD and MET. In addition, intestinal CaSR, p-AMPK/AMPK and tight junction protein claudin-1 expressions were downregulated in HFD which were upregulated by COS10 and MET. Renal TNFαR activation and increased proinflammatory cytokines were detected in HFD. Moreover, renal apoptosis markers, Bcl-2-associated X protein (Bax) and cleaved caspase-3, were increased, along with the suppressing of anti-apoptotic B-cell lymphoma-2 (Bcl-2) in HFD. Treatment with COS10 or MET markedly alleviated renal inflammation and apoptosis. CONCLUSION: COS exerted renoprotection through attenuating renal inflammation and apoptosis as a result of improving intestinal barrier via CaSR/AMPK activation and lipid absorption in obese rats. Therefore, COS might be an effective new dietary supplement for treating obesity and its related complications in clinical use.