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Cytosolic phospholipase A2? increases proliferation and de-differentiation of human renal tubular epithelial cells.

ABSTRACT: The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2?) enzyme controls the release of arachidonic acid from membrane bound phospholipids and is the rate-limiting step in production of eicosanoids. A variety of different kidney injuries activate cPLA2?, therefore we hypothesized that cPLA2? activity would regulate pathologic processes in HK-2 cells, a human renal tubular epithelial cell line, by regulating cell phenotype and proliferation. In two lentiviral cPLA2?-silenced knockdowns, we observed decreased proliferation and increased apoptosis compared to control HK-2 cells. cPLA2?-silenced cells also demonstrated an altered morphology, had increased expression E-cadherin, and decreased expression of Ncadherin. Increased levels of E-cadherin were associated with increased promoter activity and decreased levels of SNAIL1, SNAIL2, and ZEB1, transcriptional repressors of E-cadherin expression. Addition of exogenous arachidonic acid, but not PGE2, reversed the phenotypic changes in cPLA2?-silenced cells. These data suggest that cPLA2? may play a key role in renal repair after injury through a PGE2-independent mechanism.

SUBMITTER: Montford JR

PROVIDER: S-EPMC5099119 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Cytosolic phospholipase A2α increases proliferation and de-differentiation of human renal tubular epithelial cells.

Montford John R JR Lehman Allison M B AM Scobey Micah S MS Weiser-Evans Mary C M MC Nemenoff Raphael A RA Furgeson Seth B SB

Prostaglandins & other lipid mediators 20160821

The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2α) enzyme controls the release of arachidonic acid from membrane bound phospholipids and is the rate-limiting step in production of eicosanoids. A variety of different kidney injuries activate cPLA2α, therefore we hypothesized that cPLA2α activity would regulate pathologic processes in HK-2 cells, a human renal tubular epithelial cell line, by regulating cell phenotype and proliferation. ...[more]

PMID: 27554058

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Project description:BackgroundThe combined effects of glyphosate and hard water on chronic kidney disease of unknown etiology (CDKu) have attracted much interest, but the mechanisms remain unknown. Cytoplasmic phospholipase A2 (cPLA2) plays a key role in the acute and chronic inflammatory reactions. This study explored the effect of glyphosate combined with hard water on renal tubules and the possible targets and mechanisms involved.MethodsIn vivo experiments were conducted to investigate the synergistic effects and potential mechanisms of glyphosate and hard water on renal tubular injury in mice.ResultsAdministration of glyphosate in mice resulted in elevated levels of β2-microglobulin (β2-MG), albumin (ALB), and serum creatinine (SCr) compared to control mice. This increase was more pronounce when glyphosate was combined with hard water. In the glyphosate-treated mice, small areas of the kidney revealed fibroblast proliferation and vacuolar degeneration, particularly at the higher dose of 400 mg/kg glyphosate. However, the combination of glyphosate and hard water induced an even greater degree of pathological changes in the kidney. Immunofluorescence and western blot analyses showed that glyphosate and hard water had a coordinated effect on calcium ions (Ca2+)-activated phospholipase A2 and the activation may play a key role in inflammation and renal tubular injury. Exposure to glyphosate alone or glyphosate plus hard water increased the levels of oxidative stress markers and inflammatory biomarkers, namely, thromboxane A2 (TX-A2), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), nitric oxide synthase (NOS), and nitric oxide (NO). Parameters of oxidative stress, including the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were decreased. Further analysis showed that the levels of these biomarkers were significantly different between the mice treated with glyphosate plus hard water and the mice treated with glyphosate alone.ConclusionsThese findings suggested that hard water combined with glyphosate can induce renal tubular injury in mice, and this may involve mitogen-activated protein kinases (MAPK)/cytosolic phospholipase A2 (cPLA2)/arachidonic acid (AA) and its downstream factors.

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Cytosolic phospholipase A2? increases proliferation and de-differentiation of human renal tubular epithelial cells.

Publications

Cytosolic phospholipase A<sub>2</sub>α increases proliferation and de-differentiation of human renal tubular epithelial cells.

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