title: Vascular smooth muscle cells contribute to APOL1-induced podocyte injury in HIV milieu.
abstract: Clinical reports have demonstrated that higher rates of non-diabetic glomerulosclerosis in African Americans can be attributed to two coding sequence variants (G1 and G2) in the APOL1 gene; however, the underlying mechanism is still unknown. Kidney biopsy data suggest enhanced expression of APOL1/APOL1 variants (Vs) in smooth muscle cells (SMCs) of renal vasculature. Since APOL1 is a secretory protein of relatively low molecular weight (41kDa), SMCs may be a contributory endocrine/paracrine source of APOL1 wild type (WT)/APOL1Vs in the glomerular capillary perfusate percolating podocytes. In the present study, we tested the hypothesis that an HIV milieu stimulated secretion of APOL1 and its risk variants by arterial SMCs contributes to podocyte injury. Human umbilical artery smooth muscle cells (HSMCs)-treated with conditioned media (CM) of HIV-infected peripheral mononuclear cells (PBMC/HIV-CM), CM of HIV-infected U939 cells, or recombinant IFN-γ displayed enhanced expression of APOL1. Podocytes co-cultured in trans-wells with HSMCs-over expressing APOL1WT showed induction of injury; however, podocytes co-cultured with HSMC-over expressing either APOL1G1 or APOL1G2 showed several folds greater injury when compared to HSMC-over expressing APOL1WT. Conditioned media collected from HSMC-over-expressing APOL1G1/APOL1G2 (HSMC/APOL1G1-CM or HSMC/APOL1G2-CM) also displayed higher percentages of injured podocytes in the form of swollen cells, leaky lysosomes, loss of viability, and enhanced sensitivity to adverse host factors when compared to HSMC/APOL1WT-CM. Notably, HSMC/APOL1WT-CM promoted podocyte injury only at a significantly higher concentrations compared to HSMC/APOL1G1/G2-CM. We conclude that HSMCs could serve as an endocrine/paracrine source of APOL1Vs, which mediate accelerated podocyte injury in HIV milieu.
authors: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Department of Medicine, Hofstra North Shore LIJ Medical School, NY, USA.
authors: Xiqian
authors: X
authors: Lan
authors: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Department of Medicine, Hofstra North Shore LIJ Medical School, NY, USA.
authors: Hongxiu
authors: H
authors: Wen
authors: Renal Academic Unit, Department of Pediatrics, University of Bristol, Bristol, UK.
authors: Moin A
authors: MA
authors: Saleem
authors: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors: Joanna
authors: J
authors: Mikulak
authors: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Department of Medicine, Hofstra North Shore LIJ Medical School, NY, USA.
authors: Ashwani
authors: A
authors: Malhotra
authors: Nephrology and Molecular Medicine, Technion Institute of Technology, Rambam Medical Center, Haifa, Israel.
authors: Karl
authors: K
authors: Skorecki
authors: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Department of Medicine, Hofstra North Shore LIJ Medical School, NY, USA. Electronic address: psinghal@nshs.edu.
authors: Pravin C
authors: PC
authors: Singhal
mesh_terms: D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006678:HIV / Q000472:pathogenicity; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D017077:Culture Media, Conditioned; D008075:Lipoproteins, HDL