1. Apolipoprotein L-1 renal risk variants form active channels at the plasma membrane driving cytotoxicity
- Author
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Enrique Rodriguez-Boulan, Jayne Raper, Nirav Malani, Patrick J. Zager, Nailya Khalizova, Russell Thomson, Ryan Schreiner, and Joseph A Giovinazzo
- Subjects
0301 basic medicine ,Apolipoprotein B ,Apolipoprotein L1 ,030232 urology & nephrology ,Endoplasmic Reticulum ,Kidney ,Ion Channels ,polymorphism ,0302 clinical medicine ,Risk Factors ,Biology (General) ,education.field_of_study ,Cell Death ,biology ,Cytotoxins ,General Neuroscience ,General Medicine ,Hydrogen-Ion Concentration ,membrane channels ,Cell biology ,Medicine ,Kidney Diseases ,Apolipoprotein L ,protein trafficking ,Research Article ,Human ,Programmed cell death ,QH301-705.5 ,Science ,Population ,CHO Cells ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Cricetulus ,medicine ,Animals ,Humans ,Human Biology and Medicine ,education ,Ion channel ,apolipoprotein l1 ,General Immunology and Microbiology ,Sodium ,Cell Membrane ,Cell Biology ,medicine.disease ,HEK293 Cells ,030104 developmental biology ,Microscopy, Fluorescence ,ion channel ,Potassium ,biology.protein ,Membrane channel ,Kidney disease - Abstract
Recently evolved alleles of Apolipoprotein L-1 (APOL1) provide increased protection against African trypanosome parasites while also significantly increasing the risk of developing kidney disease in humans. APOL1 protects against trypanosome infections by forming ion channels within the parasite, causing lysis. While the correlation to kidney disease is robust, there is little consensus concerning the underlying disease mechanism. We show in human cells that the APOL1 renal risk variants have a population of active channels at the plasma membrane, which results in an influx of both Na+and Ca2+. We propose a model wherein APOL1 channel activity is the upstream event causing cell death, and that the activate-state, plasma membrane-localized channel represents the ideal drug target to combat APOL1-mediated kidney disease.
- Published
- 2020