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

May, Carl J.; Chesor, Musleeha; Hunter, Sarah; Hayes, Bryony; Barr, Rachel; Roberts, Timothy P.L.; Barrington, Fern A; Farmer, Louise K.; Ni, Lan; Jackson, Maisie; Snethen, Heidi; Tavakolidakhrabadi, Nadia; Goldstone, Max; Gilbert, Rodney D.; Beesley, Matt; Lennon, Rachel; Foster, Rebecca R.; Coward, Richard Jm; Welsh, Gavin I.; Saleem, Moin A.

doi:10.1016/j.kint.2023.02.031

Cited by 6 publications

(2 citation statements)

References 29 publications

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“…Our own work over the years has identified excess protease activity in plasma from patients with post-transplant recurrence, using in vitro podocyte protein signalling as the biological readout [5,9,34]. Further work, implicate that overactivation of the main protease receptor, PAR-1, on podocytes leads to the same cellular signalling pathway activation and podocyte disruption including FSGS in experimental mice [9,35]. This raises the possibility that an imbalance of circulating proteases could underlie the pathogenesis of CFD.…”

Section: Proteases As Candidate Circulating Factor Proteinsmentioning

confidence: 98%

What is circulating factor disease and how is it currently explained?

2023

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Nephrotic syndrome (NS) consists of the clinical triad of hypoalbuminaemia, high levels of proteinuria and oedema, and describes a heterogeneous group of disease processes with different underlying drivers. The existence of circulating factor disease (CFD) as a driver of NS has been epitomised by a subset of patients who exhibit disease recurrence after transplantation, alongside laboratory work. Several circulating factors have been proposed and studied, broadly grouped into protease components such as soluble urokinase-type plasminogen activator (suPAR), hemopexin (Hx) and calcium/calmodulin-serine protease kinase (CASK), and other circulating proteases, and immune components such as TNF-α, CD40 and cardiotrophin-like cytokine-1 (CLC-1). While currently there is no definitive way of assessing risk of CFD pre-transplantation, promising work is emerging through the study of ‘multi-omic’ bioinformatic data from large national cohorts and biobanks.

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Section: Proteases As Candidate Circulating Factor Proteinsmentioning

confidence: 98%

What is circulating factor disease and how is it currently explained?

2023

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“…Primary forms of adult MCD and FSGS present with a similar extent of proteinuria, but often exhibit a different disease course with immediate steroid response in MCD and a slower/absent response in FSGS. Activation of protease activated receptor 1 (PAR-1) [ 2 ], a podocyte membrane protein, has been suggested as a key initiator of the presumed circulating soluble factor, responsible to initiate FSGS. There is emerging evidence that a subset of patients with MCD have autoantibodies against podocyte proteins (for example, nephrin), providing potential links between podocyte injury, autoimmunity, and proteinuria response to anti-B-cell treatment [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group

Mirioglu,

Daniel-Fischer,

Berke

et al. 2024

Nephrology Dialysis Transplantation

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The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), are entities without immune complex deposits which can cause podocyte injury, thus frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA), and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.

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