Title
Tubular cell phenotype in HIV-associated nephropathy: Role of phospholipid lysophosphatidic acid
Publication Date
2015
Journal Title
Exp Mol Pathol
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 NF kappa B 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) alpha-smooth muscle actin (alpha-SMA; 12 fold), and d) collagen 1(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-kappa B; whereas, a LPA biosynthesis inhibitor (AACOCF3), a DAG kinase inhibitor, a LPA receptor blocker (Ki16425), a NF-kappa B inhibitor (PDTC) and NF kappa B-siRNA not only displayed downregulation of a NF kappa B 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 NF kappa B activation in HIVAN. (C) 2015 Elsevier Inc. All rights reserved.
Volume Number
99
Issue Number
1
Pages
109-115
Document Type
Article
EPub Date
2015/06/17
Status
Faculty; Northwell Researcher
Facility
School of Medicine; Northwell Health
Primary Department
Nephrology
PMID
DOI
10.1016/j.yexmp.2015.06.004