Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 317, Issue 2, Pages C209-C225Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00538.2018
Keywords
APOL1; autophagy; dedifferentiation of podocytes; miR193a; podocytes
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [RO1 DK-098074, RO1 DK-118017]
- Israel Science Foundation [ISF 182/15]
- Rambam Medical Center, Kaylie Kidney Health Center of Excellence
- Beutler Foundation for Genomic Medicine Research
- MRC [G0800200, MR/R003017/1, G0800571, MR/L002418/1, MR/R013942/1, MR/P024297/1] Funding Source: UKRI
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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 APOLIG0 (G0-podocytes) showed downregulation but podocyte-expressing APOLIG1 (Gl-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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