TitleTransgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.
Publication TypeJournal Article
Year of Publication2017
AuthorsBeckerman P, Bi-Karchin J, Park ASeo Deok, Qiu C, Dummer PD, Soomro I, Boustany-Kari CM, Pullen SS, Miner JH, Hu C-AA, Rohacs T, Inoue K, Ishibe S, Saleem MA, Palmer MB, Cuervo AMaria, Kopp JB, Susztak K
JournalNat Med
Volume23
Issue4
Pagination429-438
Date Published2017 Apr
ISSN1546-170X
KeywordsAlbuminuria, Alleles, Animals, Apolipoprotein L1, Apolipoproteins, Autophagy, Azotemia, Blotting, Western, Endocytosis, Endosomes, Fluorescent Antibody Technique, Genetic Predisposition to Disease, Genetic Variation, Glomerulosclerosis, Focal Segmental, HEK293 Cells, HeLa Cells, Humans, Immunohistochemistry, In Situ Nick-End Labeling, Kidney Glomerulus, Lipoproteins, HDL, Mice, Mice, Transgenic, Microscopy, Electron, Podocytes, Renal Insufficiency, Chronic
Abstract

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.

DOI10.1038/nm.4287
Alternate JournalNat. Med.
PubMed ID28218918
PubMed Central IDPMC5603285
Grant ListG0800571 / / Medical Research Council / United Kingdom
R21 DK095419 / DK / NIDDK NIH HHS / United States
DP3 DK108220 / DK / NIDDK NIH HHS / United States
R01 DK078314 / DK / NIDDK NIH HHS / United States
T32 DK007785 / DK / NIDDK NIH HHS / United States
R01 DK087635 / DK / NIDDK NIH HHS / United States
R01 DK083294 / DK / NIDDK NIH HHS / United States
R01 NS055159 / NS / NINDS NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
RF1 AG054108 / AG / NIA NIH HHS / United States
R01 DK093629 / DK / NIDDK NIH HHS / United States
P30 AG038072 / AG / NIA NIH HHS / United States
R01 GM093290 / GM / NIGMS NIH HHS / United States
P30 CA013330 / CA / NCI NIH HHS / United States
R01 DK076077 / DK / NIDDK NIH HHS / United States
MR/L002418/1 / / Medical Research Council / United Kingdom
P01 AG031782 / AG / NIA NIH HHS / United States
T32 DK007006 / DK / NIDDK NIH HHS / United States
R01 DK105821 / DK / NIDDK NIH HHS / United States
R01 DK058366 / DK / NIDDK NIH HHS / United States