Activation of necroptosis pathway in podocyte contributes to the pathogenesis of focal segmental glomerular sclerosis

Background Focal segmental glomerulosclerosis (FSGS) is characterized by podocyte damage and severe proteinuria. The exact mechanism of podocyte damage and loss remains unclear. Necroptosis, a lytic form of programmed cell death mediated by RIP3 and MLKL, has emerged as an important cell death pattern in multiple tissues and cell types. Necroptosis in FSGS has not been investigated. Methods Public GEO data regarding podocyte treated with vehicle or adriamycin (ADR) was identified and analyzed. Cultured human podocytes were used to explore the activation of necroptosis upon ADR stimulation. The expression of necroptosis pathway molecules, p-RIP3 and p-MLKL, was examined in the glomeruli and defoliated urinary podocytes of patients with FSGS. The effect of necroptosis inhibition was assessed in ADR-induced glomerulopathy mice using GSK872. Results Publicly available RNA-sequencing data analysis showed that both necroptosis and NLRP3 inflammasome pathway were up-regulated in ADR-injured podocyte. Immunofluorescent staining showed increased expression of p-RIP3 and p-MLKL, the active forms of RIP3 and MLKL, in podocytes of FSGS patients and ADR-induced glomerulopathy mice but not in the normal control. GSK872, an RIP3 kinase inhibitor, significantly inhibited the expression of p-RIP3, p-MLKL and activation of NLRP3 in cultured podocytes treated with ADR. GSK872 treatment of mice with ADR-induced nephropathy resulted in the reduced expression of p-RIP3, p-MLKL, NLRP3 and caspase-1 p20. GSK872 also significantly inhibited the expression of p-MLKL in the podocytes of ADR-induced nephropathy, resulting in the attenuation of proteinuria and renal histological lesions. Conclusion Necroptosis pathway might be a valuable target for the treatment of FSGS..

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:26

Enthalten in:

Clinical and experimental nephrology - 26(2022), 11 vom: 04. Aug., Seite 1055-1066

Sprache:

Englisch

Beteiligte Personen:

Hu, Haoqiang [VerfasserIn]
Li, Mengyuan [VerfasserIn]
Chen, Binfeng [VerfasserIn]
Guo, Chaohuan [VerfasserIn]
Yang, Niansheng [VerfasserIn]

Links:

Volltext [lizenzpflichtig]

BKL:

44.88$jUrologie$jNephrologie

Themen:

Focal segmental glomerular sclerosis
Inflammasome
Necroptosis
Podocyte

Anmerkungen:

© The Author(s), under exclusive licence to The Japanese Society of Nephrology 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

doi:

10.1007/s10157-022-02258-1

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2132403635

Zugang & Verfügbarkeit




Zugehörige Publikationen/Bände

    Haven't found what you're looking for?