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Disrupted apolipoprotein L1-miR193a axis dedifferentiates podocytes through autophagy blockade in an APOL1 risk milieu.
Kumar, Vinod; Ayasolla, Kamesh; Jha, Alok; Mishra, Abheepsa; Vashistha, Himanshu; Lan, Xiqian; Qayyum, Maleeha; Chinnapaka, Sushma; Purohit, Richa; Mikulak, Joanna; Saleem, Moin A; Malhotra, Ashwani; Skorecki, Karl; Singhal, Pravin C.
Afiliación
  • Kumar V; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Ayasolla K; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Jha A; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Mishra A; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Vashistha H; Ochsner Clinic , New Orleans, Louisiana.
  • Lan X; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Qayyum M; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Chinnapaka S; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Purohit R; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Mikulak J; Humanitas Clinical and Research Center, Rozzano, Milan , Italy.
  • Saleem MA; Academic Renal Unit, University of Bristol , Bristol , United Kingdom.
  • Malhotra A; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
  • Skorecki K; Technion-Israel Institute of Technology, Rambam Health Care Campus, Haifa , Israel.
  • Singhal PC; Feinstein Institute and Zucker School of Medicine at Hofstra-Northwell , Hempstead, New York.
Am J Physiol Cell Physiol ; 317(2): C209-C225, 2019 08 01.
Article en En | MEDLINE | ID: mdl-31116585
We hypothesized that a functional apolipoprotein LI (APOL1)-miR193a axis (inverse relationship) preserves, but disruption alters, the podocyte molecular phenotype through the modulation of autophagy flux. Podocyte-expressing APOL1G0 (G0-podocytes) showed downregulation but podocyte-expressing APOL1G1 (G1-podocytes) and APOL1G2 (G2-podocytes) displayed enhanced miR193a expression. G0-, G1-, and G2-podocytes showed enhanced expression of light chain (LC) 3-II and beclin-1, but a disparate expression of p62 (low in wild-type but high in risk alleles). G0-podocytes showed enhanced, whereas G1- and G2-podocytes displayed decreased, phosphorylation of Unc-51-like autophagy-activating kinase (ULK)1 and class III phosphatidylinositol 3-kinase (PI3KC3). Podocytes overexpressing miR193a (miR193a-podocytes), G1, and G2 showed decreased transcription of PIK3R3 (PI3KC3's regulatory unit). Since 3-methyladenine (3-MA) enhanced miR193a expression but inhibited PIK3R3 transcription, it appears that 3-MA inhibits autophagy and induces podocyte dedifferentiation via miR193a generation. miR193a-, G1-, and G2-podocytes also showed decreased phosphorylation of mammalian target of rapamycin (mTOR) that could repress lysosome reformation. G1- and G2-podocytes showed enhanced expression of run domain beclin-1-interacting and cysteine-rich domain-containing protein (Rubicon); however, its silencing prevented their dedifferentiation. Docking, protein-protein interaction, and immunoprecipitation studies with antiautophagy-related gene (ATG)14L, anti-UV radiation resistance-associated gene (UVRAG), or Rubicon antibodies suggested the formation of ATG14L complex I and UVRAG complex II in G0-podocytes and the formation of Rubicon complex III in G1- and G2-podocytes. These findings suggest that the APOL1 risk alleles favor podocyte dedifferentiation through blockade of multiple autophagy pathways.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / MicroARNs / Podocitos / Desdiferenciación Celular / Apolipoproteína L1 Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Physiol Cell Physiol Asunto de la revista: FISIOLOGIA Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / MicroARNs / Podocitos / Desdiferenciación Celular / Apolipoproteína L1 Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Physiol Cell Physiol Asunto de la revista: FISIOLOGIA Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos