Gao Pan, He Fang-Fang, Tang Hui, Lei Chun-Tao, Chen Shan, Meng Xian-Fang, Su Hua, Zhang Chun
Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
J Diabetes Res. 2015;2015:504761. doi: 10.1155/2015/504761. Epub 2015 Mar 5.
Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease, and previously we demonstrated that NALP3 inflammasome was involved in the pathogenesis of DN. Here we investigated the mechanisms of NALP3 inflammasome activation in podocyte injury during DN. We found that, besides the activation of NALP3 inflammasome and upregulated thioredoxin-interacting protein (TXNIP), the glomerular expression of gp91 (phox) , a subunit of NADPH oxidase, was enhanced in DN mice simultaneously. Inhibiting NADPH oxidase abrogated NALP3 inflammasome activation, and IL-1β production and eventually protected podocytes from high glucose- (HG-) induced injury. TXNIP, an inhibitor of thioredoxin, acts as a suppressor for antioxidant defense system. Our observation indicated that in HG-exposed podocytes genetic deletion of TXNIP by shRNA reversed gp91 (phox) overexpression and alleviated the injury of podocyte. Collectively, our findings proposed that HG-induced NADPH oxidase activation was driven by TXNIP which subsequently triggered NALP3 inflammasome activation in podocytes and ultimately led to podocyte injury, and blocking TXNIP/NADPH oxidase signaling may be a promising treatment for DN.
糖尿病肾病（DN）是终末期肾病的主要病因之一，此前我们证明NALP3炎性小体参与了DN的发病机制。在此，我们研究了DN过程中足细胞损伤时NALP3炎性小体激活的机制。我们发现，除了NALP3炎性小体激活和硫氧还蛋白相互作用蛋白（TXNIP）上调外，DN小鼠肾小球中NADPH氧化酶亚基gp91（phox）的表达同时增强。抑制NADPH氧化酶可消除NALP3炎性小体激活和IL-1β产生，并最终保护足细胞免受高糖（HG）诱导的损伤。TXNIP作为硫氧还蛋白的抑制剂，是抗氧化防御系统的抑制因子。我们的观察表明，在暴露于HG的足细胞中，通过短发夹RNA（shRNA）对TXNIP进行基因缺失可逆转gp91（phox）的过表达并减轻足细胞损伤。总体而言，我们的研究结果表明，HG诱导的NADPH氧化酶激活由TXNIP驱动，TXNIP随后触发足细胞中NALP3炎性小体激活并最终导致足细胞损伤，阻断TXNIP/NADPH氧化酶信号通路可能是治疗DN的一种有前景的方法。
