| Autor: |
May, Carl J., Chesor, Musleeha, Hunter, Sarah E., Hayes, Bryony, Barr, Rachel, Roberts, Tim, Barrington, Fern A., Farmer, Louise, Ni, Lan, Jackson, Maisie, Snethen, Heidi, Tavakolidakhrabadi, Nadia, Goldstone, Max, Gilbert, Rodney, Beesley, Matt, Lennon, Rachel, Foster, Rebecca, Coward, Richard, Welsh, Gavin I., Saleem, Moin A. |
| Zdroj: |
Kidney International; 20230101, Issue: Preprints |
| Abstrakt: |
About 30% of patients who have a kidney transplant with underlying nephrotic syndrome (NS) experience rapid relapse of disease in their new graft. This is speculated to be due to a host-derived circulating factor acting on podocytes, the target cells in the kidney, leading to focal segmental glomerulosclerosis (FSGS). Our previous work suggests that podocyte membrane protease receptor 1 (PAR-1) is activated by a circulating factor in relapsing FSGS. Here, the role of PAR-1 was studied in human podocytes in vitro, and using a mouse model with developmental or inducible expression of podocyte-specific constitutively active PAR-1, and using biopsies from patients with nephrotic syndrome. In vitropodocyte PAR-1 activation caused a pro-migratory phenotype with phosphorylation of the kinase JNK, VASP protein and docking protein Paxillin. This signaling was mirrored in podocytes exposed to patient relapse-derived NS plasma and in patient disease biopsies. Both developmental and inducible activation of transgenic PAR-1 (NPHS2 Cre PAR-1Active+/−) caused early severe nephrotic syndrome, FSGS, kidney failure and, in the developmental model, premature death. We found that the non-selective cation channel protein TRPC6 could be a key modulator of PAR-1 signaling and TRPC6 knockout in our mouse model significantly improved proteinuria and extended lifespan. Thus, our work implicates podocyte PAR-1 activation as a key initiator of human NS circulating factor and that the PAR-1 signaling effects were partly modulated through TRPC6. |
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