基于肾周脂肪棕色化-SIRT1-HO-1/脂联素轴正反馈环路探讨Irisin保护肥胖相关性肾病的研究

Perirenal adipose tissue (PRAT) has both characteristics of white and brown fat In obesity, PRAT, with more characteristics of white adipose tissues, leads to uncoupling of glomerular vascular endothelial growth factor - nitric oxide (VEGF-NO) axis and endothelial dysfunction through lipid toxicity, which is one of the mechanisms of obesity-related glomerulopathy. Under the support of the National Natural Science Foundation of China, we demonstrated that upregulation of heme oxygenase-1 (HO-1)/adiponectin axis had dual protective effects on kidney-vessels by reversing these pathological changes; Irisin improved anti-contractile response and endothelial function by promoting browning of perivascular adipose tissue (PVAT) and upregulating HO-1/adiponectin axis in PVAT. However, it is unclear whether irisin can protect against obesity-related glomerulopathy by regulating the PRAT-vascular axis as in the regulation of PVAT-vascular axis. Therefore, in the present study, we explore the protective effects of irisin on obesity-related glomerulopathy from the new perspective of PRAT-vascular axis. We intent to demonstrate that irisin improves the imbalance of glomerular VEGF-NO axis and has dual protection of kidney-vessels by activating the positive feedback loop of PRAT browning-SIRT1-HO-1/adiponectin axis This could provide the new ideas and therapeutic targets for the prevention and treatment of obesity-related glomerulopathy.

肾周脂肪兼有白色和棕色脂肪特性。肥胖时白色脂肪特性占主导，通过脂毒性导致肾小球VEGF-NO轴失衡以及内皮损伤参与肥胖相关性肾病早期损伤。我们前期在NSFC支持下证实：上调血红素加氧酶-1（HO-1）/脂联素轴通过逆转上述病理改变对肾脏-血管起双重保护作用；肌肉因子Irisin通过促进血管周围脂肪棕色化和上调HO-1/脂联素轴，改善抗血管收缩反应及内皮功能。然而，尚不清楚Irisin是否可以类似于调控血管周围脂肪-血管轴那样，调控肾周脂肪-血管轴，对肥胖相关性肾病起保护作用。因此，本课题拟在此基础上，从肾周脂肪-血管轴这个全新视角探索Irisin对肥胖相关性肾病的保护作用。证实Irisin通过激活肾周脂肪棕色化-SIRT1-HO-1/脂联素轴正反馈环路，调控肾周脂肪-血管轴，纠正肾小球VEGF-NO轴失衡，对肾脏-血管起双重保护作用的假说，为防治肥胖相关性肾病早期损伤提供新思路和药物靶点。

肥胖相关性肾病的发病机制非常复杂，目前尚未完全阐明。我们在前一个NSFC支持下证实肾周脂肪增多可以通过肾脏脂毒性导致慢性肾脏损伤，其机制与肾周脂肪增多释放的游离脂肪酸导致的肾小球血管内皮生长因子-一氧化氮（VEGF-NO）轴失衡有关。肾周脂肪和血管周围脂肪组织类似，兼有白色和棕色脂肪特性。我们前期实验证实肌肉因子Irisin通过促进血管周围脂肪棕色化，改善抗血管收缩反应及内皮功能从而保护血管。然而，尚不清楚Irisin是否类似于调控血管周围脂肪-血管轴那样，促进肾周脂肪棕色化，调控肾周脂肪-肾小球轴，对肥胖相关性肾病起保护作用。因此，本研究旨在从肾周脂肪-血管轴这个全新视角探索Irisin对肥胖相关性肾病的保护作用及其机制。.本研究结果发现Irisin可以减少肥胖小鼠体重、脂肪含量、改善糖代谢；同时降低肥胖小鼠尿白蛋白量，减少肾脏脂质沉积，减轻肾脏纤维化及慢性肾脏损伤，对肥胖相关性慢性肾脏损伤的肾脏起保护作用。进一步机制研究发现Irisin激活肥胖小鼠肾周脂肪组织UCP-1、SIRT1和HO-1蛋白，降低肾小球VEGF水平，增加NO水平。体外实验发现类似的结果，证实这种保护机制不依赖于体重、代谢的改善，而是依赖于肾周脂肪组织的棕色化。.该研究证实Irisin可以通过促进肾周脂肪棕色化，激活肾周脂肪SIRT1-HO-1轴正反馈环路，调控肾周脂肪-血管轴，纠正肾小球VEGF-NO轴失衡，减轻肥胖相关性肾病的慢性肾脏损伤。上述研究工作顺利地达到了项目预期研究目标，共发表SCI收录论文32篇，北大核心期刊1篇，受邀参与欧洲糖尿病（EASD）年会10次，在次基础上申请NSFC面上项目1项（82170865）。研究成果有望深化棕色脂肪组织-慢性肾脏疾病之间病理生理联系及相关信号通路的认识，为防治肥胖相关性肾病早期损伤提供新思路和药物靶点。