African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.
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Work performed in the Susztak lab is supported by US National Institutes of Health (NIH) grants DK105821, DK087635, DK076077 and DP3 DK108220. The human kidney RNA-sequencing project was performed in collaboration with Boehringer Ingelheim. J. Bi-Karchin was supported by 2T32DK007006. J.B. Kopp. and P.D.D. were supported by the Intramural Research Program, NIDDK, NIH. J.H.M. was supported by R01DK078314 and R01DK058366; T.R. by GM093290 and NS055159; and A.M.C. by AG054108 (NIH). M.A.S. was supported by Kids Kidney Research, and the Bristol Nutrition NIHR-BRU. We would also like to thank the Electron Microscopy Resource Laboratory (EMRL) core facility at the University of Pennsylvania for technical support.
The Susztak lab is supported in part by Boehringer Ingelheim for a study related to the human data presented in the paper.
Supplementary Figures 1–9 and Supplementary Tables 1–4 (PDF 11328 kb)
APOL1 is colocalized to the late endosome. Spinning disc confocal microscopy movie of GFP-APOL1(green) and RFPRab7 (late endosome, red). Scale bar: 5μm. (AVI 3516 kb)
Risk allele APOL1 shows increased accumulation of recycling endosome. Spinning disc confocal microscopy movies of GFP-APOL1-G0 (AVI 3516 kb)
Risk allele APOL1 shows increased accumulation of recycling endosome. Spinning disc confocal microscopy movies of GFP-APOL1-G2 (green) and RFPRab11 (recycling endosome, red), Scale bar: 5μm. (AVI 3341 kb)
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Beckerman, P., Bi-Karchin, J., Park, A. et al. Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 23, 429–438 (2017). https://doi.org/10.1038/nm.4287
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