title: Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.
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.
authors.affiliation: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Pazit
authors.initials: P
authors.lastname: Beckerman
authors.affiliation: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Bi-Karchin
authors.affiliation: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ae Seo Deok
authors.initials: AS
authors.lastname: Park
authors.affiliation: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Chengxiang
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Dummer
authors.affiliation: Division of Nephrology, New York University, New York, New York, USA.
authors.forename: Irfana
authors.initials: I
authors.lastname: Soomro
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.
authors.forename: Carine M
authors.initials: CM
authors.lastname: Boustany-Kari
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Pullen
authors.affiliation: Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.affiliation: Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine and Health Sciences Center, Albuquerque, New Mexico, USA.
authors.forename: Chien-An A
authors.initials: CA
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Physiology &Neuroscience, Rutgers-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Tibor
authors.initials: T
authors.lastname: Rohacs
authors.affiliation: Division of Nephrology, Yale University, School of Medicine, New Haven, Connecticut, USA.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Nephrology, Yale University, School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shuta
authors.initials: S
authors.lastname: Ishibe
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Palmer
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Ana Maria
authors.identifier: http://orcid.org/0000-0002-0771-700X
authors.initials: AM
authors.lastname: Cuervo
authors.affiliation: Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Susztak
mesh_terms: D000419:Albuminuria / Q000235:genetics; D000483:Alleles; D000818:Animals; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D001343:Autophagy / Q000235:genetics; D053099:Azotemia / Q000235:genetics; D015153:Blotting, Western; D004705:Endocytosis / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000473:pathology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008075:Lipoproteins, HDL / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D050199:Podocytes / Q000378:metabolism* / Q000648:ultrastructure; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000473:pathology
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL