Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events

Carl J May, Musleeha Chesor, Sarah E Hunter, Bryony Hayes, Rachel Barr, Tim Roberts, Fern A Barrington, Louise Farmer, Lan Ni, Maisie Jackson , Heidi Snethen, Nadia Tavakolidakhrabadi, Max Goldstone, Rodney Gilbert, Matt Beesley, Rachel Lennon, Rebecca Foster, Richard Coward, Gavin I Welsh, Moin A Saleem*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)

Abstract

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 vitro podocyte 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-1 active+/-) 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.

Original languageEnglish
Pages (from-to)265-278
Number of pages14
JournalKidney International
Volume104
Issue number2
Early online date18 Mar 2023
DOIs
Publication statusE-pub ahead of print - 18 Mar 2023

Bibliographical note

Funding Information:
This work was funded by a Kidney Research UK PhD Studentship Award. CJM was additionally funded by Medical Research Council (MRC) awards MRC MR/R003017/1 and MRC MR/L002418/1. We also gratefully acknowledge financial support for this work from the Nephrotic Syndrome Trust (NEST; www.nstrust.co.uk ).

Publisher Copyright:
© 2023

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