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J Am Soc Nephrol. 2017 Apr;28(4):1093-1105. doi: 10.1681/ASN.2016050567. Epub 2016 Nov 7.

APOL1 Renal-Risk Variants Induce Mitochondrial Dysfunction.

Author information

1
Department of Internal Medicine, Section on Nephrology, lima@wakehealth.edu bfreedma@wakehealth.edu.
2
Center for Public Health Genomics.
3
Division of Public Health Sciences, Department of Biostatistical Sciences.
4
Department of Internal Medicine, Section on Nephrology.
5
Department of Internal Medicine, Section on Gerontology and Geriatric Medicine.
6
Department of Cancer Biology.
7
Department of Internal Medicine, Section on Molecular Medicine.
8
Department of Physiology and Pharmacology.
9
Department of Biochemistry.
10
Department of Urology, and.
11
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Abstract

APOL1 G1 and G2 variants facilitate kidney disease in blacks. To elucidate the pathways whereby these variants contribute to disease pathogenesis, we established HEK293 cell lines stably expressing doxycycline-inducible (Tet-on) reference APOL1 G0 or the G1 and G2 renal-risk variants, and used Illumina human HT-12 v4 arrays and Affymetrix HTA 2.0 arrays to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics analyses involved mitochondrial function; results from immunoblotting, immunofluorescence, and functional assays validated these findings. Overexpression of APOL1 by doxycycline induction in HEK293 Tet-on G1 and G2 cells led to impaired mitochondrial function, with markedly reduced maximum respiration rate, reserve respiration capacity, and mitochondrial membrane potential. Impaired mitochondrial function occurred before intracellular potassium depletion or reduced cell viability occurred. Analysis of global gene expression profiles in nondiseased primary proximal tubule cells from black patients revealed that the nicotinate phosphoribosyltransferase gene, responsible for NAD biosynthesis, was among the top downregulated transcripts in cells with two APOL1 renal-risk variants compared with those without renal-risk variants; nicotinate phosphoribosyltransferase also displayed gene expression patterns linked to mitochondrial dysfunction in HEK293 Tet-on APOL1 cell pathway analyses. These results suggest a pivotal role for mitochondrial dysfunction in APOL1-associated kidney disease.

KEYWORDS:

APOL1; chronic kidney disease; mitochondria

Comment in

PMID:
27821631
PMCID:
PMC5373457
DOI:
10.1681/ASN.2016050567
[Indexed for MEDLINE]
Free PMC Article

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