| First Author | Li J | Year | 2022 |
| Journal | Cell Death Differ | Volume | 29 |
| Issue | 12 | Pages | 2399-2416 |
| PubMed ID | 35710882 | Mgi Jnum | J:332964 |
| Mgi Id | MGI:7410777 | Doi | 10.1038/s41418-022-01026-8 |
| Citation | Li J, et al. (2022) B7-1 mediates podocyte injury and glomerulosclerosis through communication with Hsp90ab1-LRP5-beta-catenin pathway. Cell Death Differ 29(12):2399-2416 |
| abstractText | 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. |
