title: Tubular cell phenotype in HIV-associated nephropathy: role of phospholipid lysophosphatidic acid.
abstract: Collapsing glomerulopathy and microcysts are characteristic histological features of HIV-associated nephropathy (HIVAN). We have previously reported the role of epithelial mesenchymal transition (EMT) in the development of glomerular and tubular cell phenotypes in HIVAN. Since persistent tubular cell activation of NFκB has been reported in HIVAN, we now hypothesize that HIV may be contributing to tubular cell phenotype via lysophosphatidic acid (LPA) mediated downstream signaling. Interestingly, LPA and its receptors have also been implicated in the tubular interstitial cell fibrosis (TIF) and cyst formation in autosomal dominant polycystic kidney disease (PKD). Primary human proximal tubular cells (HRPTCs) were transduced with either empty vector (EV/HRPTCs), HIV (HIV/HRPTCs) or treated with LPA (LPA/HRPTC). Immunoelectrophoresis of HIV/HRPTCs and LPA/HRPTCs displayed enhanced expression of pro-fibrotic markers: a) fibronectin (2.25 fold), b) connective tissue growth factor (CTGF; 4.8 fold), c) α-smooth muscle actin (α-SMA; 12 fold), and d) collagen I (5.7 fold). HIV enhanced tubular cell phosphorylation of ILK-1, FAK, PI3K, Akt, ERKs and P38 MAPK. HIV increased tubular cell transcriptional binding activity of NF-κB; whereas, a LPA biosynthesis inhibitor (AACOCF3), a DAG kinase inhibitor, a LPA receptor blocker (Ki16425), a NF-κB inhibitor (PDTC) and NFκB-siRNA not only displayed downregulation of a NFκB activity but also showed attenuated expression of profibrotic/EMT genes in HIV milieu. These findings suggest that LPA could be contributing to HIV-induced tubular cell phenotype via NFκB activation in HIVAN.
authors.affiliation: Department of Medicine, Hofstra North-Shore LIJ Medical School, Feinstein Institute for Medical Research, NY, United States.
authors.forename: Kamesh R
authors.initials: KR
authors.lastname: Ayasolla
authors.affiliation: Department of Medicine, Hofstra North-Shore LIJ Medical School, Feinstein Institute for Medical Research, NY, United States.
authors.forename: Partab
authors.initials: P
authors.lastname: Rai
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Rahimipour
authors.affiliation: Jamia Millia Islamia, New Delhi, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Department of Medicine, Hofstra North-Shore LIJ Medical School, Feinstein Institute for Medical Research, NY, United States.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Department of Medicine, Hofstra North-Shore LIJ Medical School, Feinstein Institute for Medical Research, NY, United States. Electronic address: PSinghal@nshs.edu.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000235:genetics / Q000473:pathology*; D000199:Actins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D005822:Genetic Vectors; D006801:Humans; D007678:Kidney Glomerulus / Q000166:cytology*; D007684:Kidney Tubules / Q000166:cytology*; D008246:Lysophospholipids / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D000199:Actins; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D005353:Fibronectins; D051417:Focal Adhesion Kinase 1; D008246:Lysophospholipids; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D014746:Vimentin; D048051:p38 Mitogen-Activated Protein Kinases; D000099200:Scaffold Protein ILK; C541116:ACTA2 protein, human; C526317:CCN2 protein, human; C496050:PTK2 protein, human; C032881:lysophosphatidic acid
keywords: Collagen-I; Connective tissue growth factor (CTGF); Epithelial mesenchymal transition (EMT); HIV associated nephropathy (HIVAN); Lysophosphatidic acid (LPA); Microcysts; Nuclear factor κB (NFκB); p-38 kinase