Research On The Mechanism Of 11β-hydroxysteroid Dehydrogenase Type 1 Inhibitor Protecting Against Renal Fibrosis In Diet-induced Obese Rats

Background: Obesity is one of the most important risk factors of many chronic diseases and can cause insulin resistance, hypertension and other metabolic disorders.Besides energy storage, the endocrine ability of adipose tissue is getting more and more attention from the society. Adipose cells can secrete a variety of factors such as fat factors and inflammatory factors to regulate the body’s physiological activities. Its secretion abnormity is closely related to the occurrence of obesity and obesity-related diseases. Obesity-related renal disease is the common one of obesity-related diseases.And renal fibrosis is the important pathologic basis in the progress to end-stage renal disease. The prevention and treatment of renal fibrosis is the key to attenuates and delay the deterioration progress of renal failure. BVT.2733 is a new selective11β-HSD1 inhibitor. Existing studies have shown that it can reduce weight, improve insulin sensitivity and reduce adipose inflammation of obese mice. There is no research of 11β-HSD1 inhibitors BVT.2733 preventing renal fibrosis and delaying the progress of end-stage renal disease in obese patients.Objective: To speculate the possible mechanisms of 11β-HSD1 inhibitors BVT.2733 treating renal fibrosis caused by high-fat diet, and to provide theoretical and experimental basis for clinical applications.Methods: Wistar rats were fed at a normal fat diet(con) or a high fat diet(HFD).HFD fed rats were then administrated with BVT.2733 for two weeks. Blood pressure was measured and oral glucose tolerance test(OGTT) was performed. HE stainingwas performed to observe adipose cells of different places(subcutaneous, beside the epididymis and kidney). Gene expressions of adipose factors, inflammation factors and fibrosis factors in adipose tissue around epididymis and renal tissue were analyzed using real-time PCR. HE staining, Masson staining and immunohistochemical staining were performed on renal tissue to observe renal fibrosis.Results:1. 11β-HSD1 inhibitor BVT. 2733 was a effective drug for the treatment of obesity and obesity-related diseases. It could not only stop the progress of obesity, but also be able to reduce the weight of rats, improve blood pressure and glucose tolerance on a high-fat diet.2. The expression of adiponectin was increased and the expression of leptin and resistin was decreased in adipose tissue after the administration of BVT. 2733.The expression of TNF-α and IL-6 in adipose tissue was reduced after using BVT.2733 treatment for 2 weeks.3. 11β-HSD1 was an important linking factor of obesity and inflammation BVT.2733 could not only improve inflammation in adipose tissue, but also reduce the expression of IL- 6, MCP – 1 in renal tissue significantly. Macrophages infiltration also reduced in renal tissue after giving BVT. 2733 treatment.4. The glomerular structure was damaged, fibroblasts in renal interstitial were stimulated and a large number of collagen Ⅰ,Ⅲ accumulated in renal tissue caused by high fat diet. After giving BVT. 2733 treatment, all the things above had been improved significantly. Quantitative PCR experiments further more proved that BVT. 2733 could significantly reduce the expression level of TGF-β、collagen-Ⅰand collagen-Ⅲ.Conclusion: 11β-HSD1 inhibitor BVT. 2733 could probably reverse renal fibrosis by reducing the weight, improving metabolism and renal inflammation, preventing activation of renal fibroblasts and collagen deposition. Our data might provide theoretical and experimental basis for the treatment of renal fibrosis in obese patients.