抑制11beta-HSD1通过RAS通路而缓解1型糖尿病肾病的机制研究

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is a key enzyme in regulating the activity and level of glucocorticoid. The inhibitors of 11beta-HSD1 could attenuate the insulin resistance and showed evident therapeutic effects on type 2 diabetes and metabolic syndrome. However, it is unknown if 11beta-HSD1 has effects on type 1 diabetes and diabetic complications. In the previous studies, we found that the hepatic expression of 11beta-HSD1 and renal expression of ACE have been increased in diabetic nephropathy mice models. Importantly, PY-01, a small-molecular specific 11beta-HSD1 regulator, could attenuate diabetic nephropathy (DN) without decreasing blood glucose in type 1 diabetic mice. This therapeutic action was accompanied with the negative regulation of renal and hepatic 11beta-HSD1 and inactivation of RAS (inhibition of ACE expression and Ang II secretion). Thus, we hypothesize here, that there is a pathological pathway "hyperglucemia → 11beta-HSD1 → RAS → nephropathy" in type 1 diabetes and PY-01 attenuates DN via this pathway. In this project, we design a series of experiments in vitro and in vivo and try to confirm our hypothesis. With the performance of this project, we will demonstrate the regulating relationship and the mediator signaling between 11beta-HSD1 and RAS. Investigation of the pharmacological molecular mechanism of PY-01 will provide a new target for the treatment of diabetic complications, and provide a new pathway for 11beta-HSD1 in diabetic complications.

11β-羟甾脱氢酶1（11β-HSD1）是调节糖皮质激素水平和活性的关键酶，在胰岛素抵抗和代谢综合征中有着重要作用。但11β-HSD1在1型糖尿病及其并发症中的作用尚无报道。我们前期发现1型糖尿病中11β-HSD1和ACE表达升高；11β-HSD1抑制剂PY-01在1型糖尿病模型中，不降低血糖但可以显著改善糖尿病肾病（DN），伴随着对肝肾组织11β-HSD1的调节和对肾素-血管紧张素系统（RAS）的抑制。基于RAS激活是肾病的重要病理因素，本项目提出，在1型糖尿病中，存在着"高血糖→11β-HSD1→RAS→肾病"的病理信号通路，而PY-01通过上述通路缓解DN。本项目中，我们拟通过一系列的细胞和动物层面上的实验证实上述通路，阐明11β-HSD1与RAS的调控关系和中间介导信号，通过挖掘PY-01的药理分子机制为糖尿病并发症提供新的治疗靶点，阐明11β-HSD1在糖尿病并发症中的新机制。

11β-羟甾脱氢酶1（11β-HSD1）是调节糖皮质激素水平和活性的关键酶，在胰岛素抵抗和代谢综合征中有着重要作用。但11β-HSD1在I型糖尿病及其并发症中的作用尚无报道。我们前期发现I型糖尿病中11β-HSD1和ACE表达升高。基于RAS激活是肾病的重要病理因素，本项目提出：在I型糖尿病中，存在着“高血糖→11β-HSD1→RAS→肾病”的病理信号通路，而LG13通过上述通路缓解DN。本项目中，我们通过一系列的细胞和动物层面上的实验证实11β-HSD1在糖尿病并发症中的重要作用，通过研究LG13的药理分子机制证实了11β-HSD1可以作为糖尿病并发症新的治疗靶点。在实验进程中，我们发现EGFR参与了11β-HSD1调控RAS的过程并证明了EGFR是11β-HSD1调控RAS中间介导信号。同时，本项目使用临床药物生胃酮对实验结果进行了验证。本项目的完成将为I型糖尿病及其并发症的防治提供新的靶点。