{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["May CJ"],"funding":["Kidney Research UK","Medical Research Council"],"pagination":["265-278"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7616342"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["104(2)"],"pubmed_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<sup>Active+/-</sup>) 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."],"journal":["Kidney international"],"pubmed_title":["Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events."],"pmcid":["PMC7616342"],"funding_grant_id":["MR/R003017/1","RP22/2012","Paed_IN_002_20190925","MR/K010492/1","ST_008_20181123","MR/W019582/1","MR/T002263/1","G0501901","G0800200","MR/L002418/1"],"pubmed_authors":["Roberts T","Ni L","Jackson M","Welsh GI","Coward R","Farmer L","Tavakolidakhrabadi N","Snethen H","Hayes B","Lennon R","May CJ","Barrington FA","Beesley M","Gilbert R","Saleem MA","Hunter SE","Goldstone M","Chesor M","Foster R","Barr R"],"additional_accession":[]},"is_claimable":false,"name":"Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events.","description":"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<sup>Active+/-</sup>) 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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Aug","modification":"2025-04-18T20:09:47.338Z","creation":"2025-04-07T08:01:45.951Z"},"accession":"S-EPMC7616342","cross_references":{"pubmed":["36940798"],"doi":["10.1016/j.kint.2023.02.031"]}}