title: Therapeutics for APOL1 nephropathies: putting out the fire in the podocyte.
abstract: APOL1 nephropathies comprise a range of clinical and pathologic syndromes, which can be summarized as focal segmental glomerulosclerosis, in various guises, and arterionephrosclerosis, otherwise known as hypertensive kidney diseases. Current therapies for these conditions may achieve therapeutic targets, reduction in proteinuria and control of blood pressure, respectively, but often fail to halt the progressive decline in kidney function. It appears that current therapies fail to address certain underlying critical pathologic processes that are driven, particularly in podocytes and microvascular cells, by the APOL1 renal risk genetic variants. Mechanisms hypothesized to be responsible for APOL1 variant-associated cell injury can be summarized in five domains: increased APOL1 gene expression, activation of inflammasomes, activation of protein kinase R, electrolyte flux across plasma or intracellular membranes, and altered endolysosomal trafficking associated with endoplasmic reticulum stress. We briefly review the available evidence for these five mechanisms and suggest possible novel therapeutic approaches.
authors.affiliation: Kidney Disease Section, NIDDK, NIH, Bethesda, MD, USA.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Heymann
authors.affiliation: Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program; Leidos Biomedical Research, Frederick National Laboratory, NCI, NIH, Frederick, MD, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Merck Research Laboratories, Merck and Co., Kenilworth, NJ, USA.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hoek
authors.affiliation: Renal, Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Susztak
authors.affiliation: Kidney Disease Section, NIDDK, NIH, Bethesda, MD, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
mesh_terms: D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000037:antagonists & inhibitors*; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008075:Lipoproteins, HDL / Q000037:antagonists & inhibitors*; D009393:Nephritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL
keywords: chronic kidney disease; focal segmental glomerulosclerosis; glomerulosclerosis; inflammation; podocytes