Your browser doesn't support javascript.
loading
A small molecule chaperone rescues keratin-8 mediated trafficking of misfolded podocin to correct genetic Nephrotic Syndrome.
Kuzmuk, Valeryia; Pranke, Iwona; Rollason, Ruth; Butler, Matthew; Ding, Wen Y; Beesley, Matthew; Waters, Aoife M; Coward, Richard J; Sessions, Richard; Tuffin, Jack; Foster, Rebecca R; Mollet, Géraldine; Antignac, Corinne; Edelman, Aleksander; Welsh, Gavin I; Saleem, Moin A.
Afiliação
  • Kuzmuk V; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK.
  • Pranke I; INSERM, U1151, Institut Necker Enfants Malades, INEM, Paris, France.
  • Rollason R; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK.
  • Butler M; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK.
  • Ding WY; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK.
  • Beesley M; Department of Pathology, Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK.
  • Waters AM; Nephrology, Great Ormond Street Hospital, London, UK.
  • Coward RJ; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK.
  • Sessions R; School of Biochemistry, University of Bristol, Bristol, UK.
  • Tuffin J; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK.
  • Foster RR; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK.
  • Mollet G; Laboratoire des Maladies Rénales Héréditaires, Inserm UMR 1163, Institut Imagine, Université Paris Cité, Paris, France.
  • Antignac C; Laboratoire des Maladies Rénales Héréditaires, Inserm UMR 1163, Institut Imagine, Université Paris Cité, Paris, France.
  • Edelman A; INSERM, U1151, Institut Necker Enfants Malades, INEM, Paris, France.
  • Welsh GI; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK.
  • Saleem MA; Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK. Electronic address: m.saleem@bristol.ac.uk.
Kidney Int ; 105(4): 744-758, 2024 Apr.
Article em En | MEDLINE | ID: mdl-37995908
Podocin is a key membrane scaffolding protein of the kidney podocyte essential for intact glomerular filtration. Mutations in NPHS2, the podocin-encoding gene, represent the commonest form of inherited nephrotic syndrome (NS), with early, intractable kidney failure. The most frequent podocin gene mutation in European children is R138Q, causing retention of the misfolded protein in the endoplasmic reticulum. Here, we provide evidence that podocin R138Q (but not wild-type podocin) complexes with the intermediate filament protein keratin 8 (K8) thereby preventing its correct trafficking to the plasma membrane. We have also identified a small molecule (c407), a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator protein defect, that interrupts this complex and rescues mutant protein mistrafficking. This results in both the correct localization of podocin at the plasma membrane and functional rescue in both human patient R138Q mutant podocyte cell lines, and in a mouse inducible knock-in model of the R138Q mutation. Importantly, complete rescue of proteinuria and histological changes was seen when c407 was administered both via osmotic minipumps or delivered orally prior to induction of disease or crucially via osmotic minipump two weeks after disease induction. Thus, our data constitute a therapeutic option for patients with NS bearing a podocin mutation, with implications for other misfolding protein disorders. Further studies are necessary to confirm our findings.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome Nefrótica Limite: Animals / Child / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome Nefrótica Limite: Animals / Child / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article