title: APOL1-G0 or APOL1-G2 Transgenic Models Develop Preeclampsia but Not Kidney Disease.
abstract: APOL1 risk variants are associated with kidney disease in blacks, but the mechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes from Tg-G0 and Tg-G2 mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia.
authors.affiliation: Division of Nephrology, Department of Medicine, MetroHealth Medical Center and leslie.bruggeman@case.edu.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bruggeman
authors.affiliation: Division of Nephrology, Department of Medicine, MetroHealth Medical Center and.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine, MetroHealth Medical Center and.
authors.forename: Liping
authors.initials: L
authors.lastname: Luo
authors.affiliation: Division of Nephrology, Department of Medicine, MetroHealth Medical Center and.
authors.forename: Sethu M
authors.initials: SM
authors.lastname: Madhavan
authors.affiliation: Division of Nephrology, Department of Medicine, MetroHealth Medical Center and.
authors.forename: Martha
authors.initials: M
authors.lastname: Konieczkowski
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota; and.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Drawz
authors.affiliation: Department of Pathology, University of Miami, Miami, Florida.
authors.forename: David B
authors.initials: DB
authors.lastname: Thomas
authors.affiliation: Department of Pathology, University of Miami, Miami, Florida.
authors.forename: Laura
authors.initials: L
authors.lastname: Barisoni
authors.affiliation: Division of Nephrology, Department of Medicine, MetroHealth Medical Center and.|Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: John R
authors.initials: JR
authors.lastname: Sedor
authors.affiliation: Division of Nephrology, Department of Medicine, MetroHealth Medical Center and.
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
mesh_terms: D000818:Animals; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D007674:Kidney Diseases / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000502:physiology; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL
keywords: chronic kidney disease; focal segmental glomerulosclerosis; genetic renal disease; podocyte; transgenic mouse