20-HETE-mediated cytotoxicity and apoptosis in ischemic kidney epithelial cells

Nilakantan, Vani; Maenpaa, Cheryl; Jia, Guangfu; Roman, Richard J.; Park, Frank

doi:10.1152/ajprenal.00387.2007

Cited by 56 publications

(52 citation statements)

References 44 publications

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“…This protection may partially involve the activation of Raf/MEK/ERK and PI3K-Akt pathways, which were shown to be protective against ischemia-reperfusion injury (11). On the contrary, we previously reported that overexpression of a 20-HETE-producing Cyp4a12 isoform was detrimental in LLC-PK 1 cells after an in vitro protocol of ischemia-reperfusion (25). Because the genetically modified LLC-PK 1 cells with the lentiviral vectors promoted constitutively, high-level production of 20-HETE (25), it is likely that there is a differential dose-dependent activation of signaling cascades resulting in the distinct biological functions of this eicosanoid, which may account for the paradoxical contradiction between these two studies.…”

Section: Discussionmentioning

confidence: 96%

20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism

Akbulut¹,

Regner²,

Roman³

et al. 2009

American Journal of Physiology-Renal Physiology

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Hydroxyeicosatetraenoic acid (20-HETE) has been reported to promote mitogenicity in a variety of cell types, including renal epithelial cells. However, the signal transduction pathways activated by 20-HETE have not been fully defined. The present study evaluated the effects of 20-HETE and its more stable agonist analogs 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5, and N- [20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE) on the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)-Akt pathway in LLC-PK1 renal epithelial cells. 20-HETE (20 M) increased phosphorylation of Raf-1 (2.5 Ϯ 0.2-fold), MEK1/2 (6.3 Ϯ 1.6-fold), and ERK1/2 (5.8 Ϯ 0.3-fold) compared with vehicle-treated cells. Similarly, the 20-HETE analogs also strongly activated ERK1/2 in a Raf-1-and MEK1/2-dependent manner. Moreover, 5,14-20-HEDE increased Akt phosphorylation by 2.2 Ϯ 0.3-fold. 20-HETE and 5,14-20-HEDE also promoted activation (Y1086) of epidermal growth factor receptor (EGFR; Y1086) by 1.9 Ϯ 0.2-and 2.5 Ϯ 0.2-fold, respectively. These effects were completely blocked by the EGFR inhibitor EKB-569 (0.1 M). Moreover, EKB-569 (0.1 M), as well as a c-Src inhibitor, SKI-606 (0.05 M), completely abolished the 20-HETE-mediated activation of the Raf/MEK/ERK and PI3K-Akt pathways. Blockade of PKC with bisindolylmaleimide I had no effect on 20-HETE-induced ERK1/2 activation. This study demonstrated that 20-HETE activated the Raf/ MEK/ERK and Akt pathways in renal epithelial cells secondary to the activation of c-Src and EGFR. epithelial cell proliferation; epidermal growth factor receptor; cell signaling 20-HYDROXYEICOSATETRAENOIC acid (20-HETE) is a lipid metabolite of arachidonic acid that is produced by -hydroxylase enzymes of the cytochrome P-450 4A (CYP4A) and 4F families (21). 20-HETE has long been known to play an integral role in the regulation of renal function, including renal vascular tone (14), tubuloglomerular feedback (49), autoregulation of renal blood flow (12,13,48), tubular transport (6,30,38,45), and mitogenesis (4,18,23,44).There has been renewed interest in 20-HETE because of its potential as a novel therapeutic target in the treatment of acute kidney injury (32), cancer (8 -10), and polycystic kidney disease (PKD) (28,29). Regner et al. (32) showed that acute administration of a 20-HETE mimetic resulted in increased renal protection following ischemia-reperfusion injury. In other studies, 20-HETE was found to play an important role as a mitogen to promote aberrant growth and proliferation in cancer cell lines in vitro (8, 9) and cystic epithelial collecting duct cells in animal models of PKD in vitro and in vivo (28,29).The mitogenic role of 20-HETE was initially documented in proximal tubular cells (18) One candidate pathway involved in cellular proliferation and survival is Raf/MEK/ERK (31). We and others found that inhibition of 20-HETE synthesis reduced ERK1/2 activation (9,10,28,29), but the mechanism by which 20-HETE stimulated this protein complex remains to be established. Studies have implicated an interac...

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Section: Discussionmentioning

confidence: 96%

20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism

Akbulut¹,

Regner²,

Roman³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…23 Cyp4a12 overexpression in renal epithelial cells leads to increased 20-HETE-mediated oxidative stress and cell apoptosis. 24 In addition, high glucose enhances Cyp4a expression and 20-HETE biosynthesis in both podocytes and proximal tubular cells, leading to cell apoptosis and hypertrophy. 15,25 In addition to its direct contribution to kidney cell function, 20-HETE could contribute to renal injury by raising BP via vascular effects.…”

Section: Discussionmentioning

confidence: 99%

Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

Gangadhariah

Luther

García

et al. 2015

Journal of the American Society of Nephrology

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In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetesmediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.

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“…Wang et al (34) recently reported antiapoptotic effects of 20-HETE in PA vascular smooth muscle cells, but no mechanisms of protection other than activation of the intrinsic pathway were reported. Nilakantan et al (26) observed enhanced ischemia-reperfusion injury in renal epithelial cells overexpressing CYP4A, an isoform that catalyzes the conversion of arachidonic acid into 20-HETE. These results may be similar to our observations of serum-starved BPAECs exposed to 50 M 20-HETE, which decreased cell numbers.…”

Section: Discussionmentioning

confidence: 99%

20-HETE increases survival and decreases apoptosis in pulmonary arteries and pulmonary artery endothelial cells

Dhanasekaran

Bodiga

Gruenloh

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Hydroxyeicosatetraenoic acid (20-HETE) is an endogenous cytochrome P-450 product present in vascular smooth muscle and uniquely located in the vascular endothelium of pulmonary arteries (PAs). 20-HETE enhances reactive oxygen species (ROS) production of bovine PA endothelial cells (BPAECs) in an NADPH oxidase-dependent manner and is postulated to promote angiogenesis via activation of this pathway in systemic vascular beds. We tested the capacity of 20-HETE or a stable analog of this compound, 20-hydroxy-eicosa-5(Z),14(Z)-dienoic acid, to enhance survival and protect against apoptosis in BPAECs stressed with serum starvation. 20-HETE produced a concentration-dependent increase in numbers of starved BPAECs and increased 5-bromo-2Ј-deoxyuridine incorporation. Caspase-3 activity, nuclear fragmentation studies, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays supported protection from apoptosis and enhanced survival of starved BPAECs treated with a single application of 20-HETE. Protection from apoptosis depended on intact NADPH oxidase, phosphatidylinositol 3 (PI3)-kinase, and ROS production. 20-HETE-stimulated ROS generation by BPAECs was blocked by inhibition of PI3-kinase or Akt activity. These data suggest 20-HETEassociated protection from apoptosis in BPAECs required activation of PI3-kinase and Akt and generation of ROS. 20-HETE also protected against apoptosis in BPAECs stressed by lipopolysaccharide, and in mouse PAs exposed to hypoxia reoxygenation ex vivo. In summary, 20-HETE may afford a survival advantage to BPAECs through activation of prosurvival PI3-kinase and Akt pathways, NADPH oxidase activation, and NADPH oxidase-derived superoxide.reduced nicotinamide adenine dinucleotide phosphatase oxidase; reactive oxygen species; phosphatidylinositol 3-kinase; Akt; hypoxia CYTOCHROME P-450 (CYP) ENZYMES can metabolize arachidonic acid into numerous eicosanoids, with the relative abundance dependent on the tissue and species (21). The major products in most tissues are the -hydroxylated metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) and regio-and stereo-specific epoxyeicosatrienoic acids. 20-HETE, a -hydroxylation product of arachidonic acid catalyzed by CYP4A, is a paracrine and autocrine mediator of numerous cellular processes (20,29,35). It is produced in vascular smooth muscle, renal, cerebral, pulmonary, mesenteric, and skeletal muscle beds and acts on the microvasculature and kidney tubules (11,18,22,33,38).Our laboratory has recently reported that 20-HETE/CYP4 enhances reactive oxygen species (ROS) production in bovine pulmonary artery (PA) endothelial cells (BPAECs) in a manner that is associated with activation of NADPH oxidase (24). 20-HETE has been linked to ROS production in other vascular beds (19), with 20-HETE-stimulated production of ROS being reported to exert either positive or negative effects in a tissueand concentration-specific manner (e.g., Refs. 9, 17). In addition, NADPH oxidase is proposed to have a key role in growth and migration of human coronary endot...

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20-HETE-mediated cytotoxicity and apoptosis in ischemic kidney epithelial cells

Cited by 56 publications

References 44 publications

20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism

20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism

Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

20-HETE increases survival and decreases apoptosis in pulmonary arteries and pulmonary artery endothelial cells

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