Kidney Disease-Associated APOL1 Variants Have Dose-Dependent, Dominant Toxic Gain-of-Function.

Journal of the American Society of Nephrology : JASN
Somenath DattaOpeyemi A Olabisi

Abstract

Two coding renal risk variants (RRVs) of the APOL1 gene (G1 and G2) are associated with large increases in CKD rates among populations of recent African descent, but the underlying molecular mechanisms are unknown. Mammalian cell culture models are widely used to study cytotoxicity of RRVs, but results have been contradictory. It remains unclear whether cytotoxicity is RRV-dependent or driven solely by variant-independent overexpression. It is also unknown whether expression of the reference APOL1 allele, the wild-type G0, could prevent cytotoxicity of RRVs. We generated tetracycline-inducible APOL1 expression in human embryonic kidney HEK293 cells and examined the effects of increased expression of APOL1 (G0, G1, G2, G0G0, G0G1, or G0G2) on known cytotoxicity phenotypes, including reduced viability, increased swelling, potassium loss, aberrant protein phosphorylation, and dysregulated energy metabolism. Furthermore, whole-genome transcriptome analysis examined deregulated canonical pathways. At moderate expression, RRVs but not G0 caused cytotoxicity in a dose-dependent manner that coexpression of G0 did not reduce. RRVs also have dominant effects on canonical pathways relevant for the cellular stress response. In HEK293 cells...Continue Reading

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Citations

Sep 18, 2020·Current Opinion in Nephrology and Hypertension·David J Cohen
Mar 2, 2021·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Jarcy ZeeMatthew G Sampson
Oct 4, 2020·Current Opinion in Nephrology and Hypertension·David J Cohen
Mar 27, 2021·Current Opinion in Nephrology and Hypertension·Leslie A BruggemanJohn F O'Toole
Apr 2, 2021·Kidney International·Barry I FreedmanKatalin Susztak
May 28, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Anne CornelissenAloke V Finn
Aug 1, 2021·The Journal of Biological Chemistry·Charles SchaubRussell Thomson
Aug 6, 2021·Disease Models & Mechanisms·Gizelle M McCarthyMartin R Pollak
Jul 1, 2021·ASAIO Journal : a Peer-reviewed Journal of the American Society for Artificial Internal Organs·Meghan E KappMarvin J Slepian
Nov 16, 2021·The Journal of Clinical Investigation·Andrew F Malone

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