APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis

Mengyuan Ge; Judith Molina; G Michelle Ducasa; Shamroop K Mallela; Javier Varona Santos; Alla Mitrofanova; Jin-Ju Kim; Xiaochen Liu; Alexis Sloan; Armando J Mendez; Santanu Banerjee; Shaoyi Liu; Hazel H Szeto; Myung K Shin; Maarten Hoek; Jeffrey B Kopp; Flavia Fontanesi; Sandra Merscher; Alessia Fornoni

doi:10.1093/hmg/ddab022

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APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis

Journal article

Peer reviewed

APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis

Mengyuan Ge, Judith Molina, G Michelle Ducasa, Shamroop K Mallela, Javier Varona Santos, Alla Mitrofanova, Jin-Ju Kim, Xiaochen Liu, Alexis Sloan, Armando J Mendez, …

Human molecular genetics, Vol.30(3-4), pp.182-197

2021-01-30

DOI: https://doi.org/10.1093/hmg/ddab022

PMID: 33517446

Abstract

Abstract Lipotoxicity was recently reported in several forms of kidney disease, including focal segmental glomerulosclerosis (FSGS). Susceptibility to FSGS in African Americans is associated with the presence of genetic variants of the Apolipoprotein L1 gene (APOL1) named G1 and G2. If and how endogenous APOL1 may alter mitochondrial function by the modifying cellular lipid metabolism is unknown. Using transgenic mice expressing the APOL1 variants (G0, G1 or G2) under endogenous promoter, we show that APOL1 risk variant expression in transgenic mice does not impair kidney function at baseline. However, APOL1 G1 expression worsens proteinuria and kidney function in mice characterized by the podocyte inducible expression of nuclear factor of activated T-cells (NFAT), which we have found to cause FSGS. APOL1 G1 expression in this FSGS-model also results in increased triglyceride and cholesterol ester contents in kidney cortices, where lipid accumulation correlated with loss of renal function. In vitro, we show that the expression of endogenous APOL1 G1/G2 in human urinary podocytes is associated with increased cellular triglyceride content and is accompanied by mitochondrial dysfunction in the presence of compensatory oxidative phosphorylation (OXPHOS) complexes elevation. Our findings indicate that APOL1 risk variant expression increases the susceptibility to lipid-dependent podocyte injury, ultimately leading to mitochondrial dysfunction.

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Collaboration types: Industry collaboration; Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.55 Urology & Nephrology - General; 1.55.352 Chronic Kidney Disease
Web Of Science research areas: Biochemistry & Molecular Biology; Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis
Creators: Mengyuan Ge - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Judith Molina - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
G Michelle Ducasa - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Shamroop K Mallela - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Javier Varona Santos - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Alla Mitrofanova - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Jin-Ju Kim - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Xiaochen Liu - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Alexis Sloan - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Armando J Mendez - Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Santanu Banerjee - Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Shaoyi Liu - Social Profit Network Research Lab, Alexandria Launch Labs, New York, New York 10016, USA
Hazel H Szeto - Social Profit Network Research Lab, Alexandria Launch Labs, New York, New York 10016, USA
Myung K Shin - Merck & Company, Inc., Kennilworth, New Jersey 07033, USA
Maarten Hoek - Merck & Company, Inc., Kennilworth, New Jersey 07033, USA
Jeffrey B Kopp - Kidney Disease Section, NIDDK, NIH, Bethesda, Maryland 20892, USA
Flavia Fontanesi - Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Sandra Merscher - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Alessia Fornoni - Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA, Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Publication Details: Human molecular genetics, Vol.30(3-4), pp.182-197
Academic Unit: Miller School of Medicine; Biochemistry & Molecular Biology Research; Diabetes Research Institute (DRI); Peggy and Harold Katz Family Drug Discovery Center; UMMG Department of Medicine; UMMG Department of Surgery; UMMG Dept of Medicine - Nephrology & Hypertension Div; UMMG Dept of Surgery - Div of Surgical Oncology
Language: English
Resource Type: Journal article
PMID: 33517446
Record Identifier: 991031599411202976