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 NFkB-siRNA not only displayed down regulation 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.

Phospholipases: at the crossroads of the immune system and the pathogenesis of HIV-1 infection

“…This effect was not observed in the presence of membrane-associated LPC or LPC produced in the membrane by PLA 2 action, thus suggesting that LPC does not prevent the formation of lipid intermediates required for fusion, but rather, it affects the binding of viral protein or proteins to target cells. Finally, an LPA receptor blocker (Ki16425), as well as an LPA biosynthesis inhibitor (AACOCF3), attenuates the HIV-1-induced expression of profibrotic markers in primary human proximal tubular cells, thus suggesting an involvement of PLA 2 in HIV-1-associated nephropathy [194].…”