B7-1 mediates podocyte injury and glomerulosclerosis through communication with Hsp90ab1-LRP5-β-catenin pathway

作者：Li, Jiemei; Niu, Jing; Min, Wenjian; Ai, Jun; Lin, Xu; Miao, Jinhua; Zhou, Shan; Liang, Ye; Chen, Shuangqin; Ren, Qian; Shen, Kunyu; Wu, Qinyu; Li, Xiaolong; Shen, Weiwei; Hou, Fan Fan; Liu, Youhua; Yang, Peng; Zhou, Lili

来源：Cell Death and Differentiation, 2022, 29(12): 2399-2416.

DOI：10.1038/s41418-022-01026-8

• MINIMAL CHANGE DISEASE
• IN-SITU HYBRIDIZATION
• CHAIN MESSENGER-RNA
• EXPRESSION
• ABATACEPT
• NEPHROPATHY
• DYSFUNCTION
• FIBROSIS

Podocyte injury is a hallmark of glomerular diseases; however, the underlying mechanisms remain unclear. B7-1 is increased in injured podocytes, but its intrinsic role is controversial. The clinical data here revealed the intimate correlation of urinary B7-1 with severity of glomerular injury. Through transcriptomic and biological assays in B7-1 transgenic and adriamycin nephropathy models, we identified B7-1 is a key mediator in podocyte injury and glomerulosclerosis through a series of signal transmission to beta-catenin. Using LC-MS/MS, Hsp90ab1, a conserved molecular chaperone, was distinguished to be an anchor for transmitting signals from B7-1 to beta-catenin. Molecular docking and subsequent mutant analysis further identified the residue K69 in the N terminal domain of Hsp90ab1 was the key binding site for B7-1 to activate LRP5/beta-catenin pathway. The interaction and biological functions of B7-1-Hsp90ab1-LRP5 complex were further demonstrated in vitro and in vivo. We also found B7-1 is a novel downstream target of beta-catenin. Our results indicate an intercrossed network of B7-1, which collectively induces podocyte injury and glomerulosclerosis. Our study provides an important clue to improve the therapeutic strategies to target B7-1.

• 单位
  南方医科大学