期刊
CELL DEATH AND DIFFERENTIATION
卷 -, 期 -, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41418-022-01026-8
关键词
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资金
- National Key R&D Program of China [2020YFC2005000]
- National Natural Science Foundation of China [82070707, 91949114]
- project of Innovation team of chronic kidney disease with integrated traditional Chinese and Western Medicine [2019KCXTD014]
- Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University [2019J013, 2021J001]
- Presidential Foundation of Nanfang Hospital [2019Z006]
- Guangdong Provincial Clinical Research Center for Kidney Disease [2020B1111170013]
This study reveals that B7-1 plays a crucial role in podocyte injury and glomerulosclerosis, transmitting signals through Hsp90ab1 to activate the beta-catenin pathway. Additionally, B7-1 is identified as a downstream target of beta-catenin. These findings provide important insights into potential therapeutic strategies targeting B7-1.
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.
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