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

Akbulut, Talha; Regner, Kevin R.; Roman, Richard J.; Avner, Ellis D.; Falck, John R.; Park, Frank

doi:10.1152/ajprenal.00146.2009

Cited by 45 publications

(42 citation statements)

References 50 publications

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“…Kidney tissue was homogenized in 1X radioimmunoprecipitation assay buffer (Millipore, Billerica, MA) with protease and phosphatase inhibitors (Pierce Biotechnology, Rockford, IL), and protein lysates were isolated after differential centrifugation. Immunoblot analysis was performed as previous published (Akbulut et al, 2009;Nadella et al, 2010;Regner et al, 2011;Kwon et al, 2012). In brief, protein lysates (25 mg) were size separated on a 4-12% NuPAGE Bis-Tris Gradient Gel (Life Technologies) and were subsequently transferred to a supported polyvinylidene difluoride membrane (Bio-Rad Laboratories, Hercules, CA).…”

Section: Methodsmentioning

confidence: 99%

G-ProteinβγSubunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

White¹,

North²,

Haines³

et al. 2014

Mol Pharmacol

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Heterotrimeric G-proteins play a crucial role in the control of renal epithelial cell function during homeostasis and in response to injury. In this report, G-protein bg subunit (Gbg) dimer activity was evaluated during the process of tubular repair after renal ischemia-reperfusion injury (IRI) in male Sprague Dawley rats. Rats were treated with a small molecule inhibitor of Gbg activity, gallein (30 or 100 mg/kg), 1 hour after reperfusion and every 24 hours for 3 additional days. After IRI, renal dysfunction was prolonged after the high-dose gallein treatment in comparison with vehicle treatment during the 7-day recovery period. Renal tubular repair in the outer medulla 7 days after IRI was significantly (P , 0.001) attenuated after treatment with high-dose gallein (100 mg/kg) in comparison with low-dose gallein (30 mg/kg), or the vehicle and fluorescein control groups. Gallein treatment significantly reduced (P , 0.05) the number of proliferating cell nuclear antigen-positive tubular epithelial cells at 24 hours after the ischemia-reperfusion phase in vivo. In vitro application of gallein on normal rat kidney (NRK-52E) proximal tubule cells significantly reduced (P , 0.05) S-phase cell cycle entry compared with vehicletreated cells as determined by 59-bromo-29-deoxyuridine incorporation. Taken together, these data suggest that Gbg signaling contributes to the maintenance and repair of renal tubular epithelium and may be a novel therapeutic target for the development of drugs to treat acute kidney injury.

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Section: Methodsmentioning

confidence: 99%

G-ProteinβγSubunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

White¹,

North²,

Haines³

et al. 2014

Mol Pharmacol

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“…Such hypothesis has been postulated for the mitogenic action of 20-HETE in renal epithelial cells. Akbulut et al (2009) showed that 20-HETE activates the Raf/MAPK kinase/extracellular signal-regulated kinase pathway in renal epithelial cells through an EGFR-and c-Src-dependent mechanism and proposed the presence of a 20-HETEspecific G-protein coupled receptor-EGFR transactivation through c-Src. To date, a receptor/binding site for 20-HETE has been implicated based on the use of specific agonists and antagonists, but it still needs to be identified.…”

Section: -Hete Induces Ace Expression Via Nf-kb Bindingmentioning

confidence: 99%

20-HETE Activates the Transcription of Angiotensin-Converting Enzyme via Nuclear Factor- B Translocation and Promoter Binding

García

Shkolnik

Milhau

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Increased vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 arachidonic acid metabolite, promotes vascular dysfunction, injury, and hypertension that is dependent, in part, on the renin angiotensin system (RAS). We have shown that, in human microvascular endothelial cells, 20-HETE increases angiotensin-converting enzyme (ACE) mRNA, protein, and ACE activity via an epidermal growth factor receptor (EGFR)/ tyrosine kinase/mitogen-activated protein kinase (MAPK)/ inhibitor of kB kinase (IKK)b-mediated signaling pathway. In this work, we show that, similar to epidermal growth factor (EGF), 20-HETE (10 nM) activates EGFR by stimulating tyrosine phosphorylation; however, unlike 20-HETE, EGF does not induce ACE expression, and pretreatment with a neutralizing antibody against EGF does not prevent the 20-HETE-mediated ACE induction. Inhibition of nuclear factor kB (NF-kB) activation prevented the 4.58-fold (60.78; P , 0.05) 20-HETE-mediated induction of ACE. The 20-HETE increased NF-kB-binding activity in nuclear extracts and the activity of both the somatic and germinal ACE promoters by 4.37-fold (60.18; P , 0.05) and 2.53-fold (6 0.24; P , 0.05), respectively. The 20-HETE-stimulated ACE promoter activity was abrogated by the 20-HETE antagonist 20-hydroxy-6,15-eicosadienoic acid and by inhibitors of EGFR, MAPK, IKKb, and NF-kB activation. Sequence analysis demonstrated the presence of two and one putative NF-kB binding sites on the human somatic and germinal ACE promoters, respectively. Chromatin immunoprecipitation assay indicated that 20-HETE stimulates the translocation and subsequent binding of NF-kB to each of the putative binding sites (S1, 3.43 6 0.3-fold enrichment versus vehicle; S2, 3.72 6 0.68-fold enrichment versus vehicle; S3, 3.20 6 0.18-fold enrichment versus vehicle; P , 0.05). This is the first study to identify NF-kB as a transcriptional factor for ACE and to implicate a distinct EGFR/MAPK/IKK/NF-kB signaling cascade underlying 20-HETE-mediated transcriptional activation of ACE mRNA and stimulation of ACE activity.

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“…The proximal tubular cell proliferative response to epidermal growth factor (EGF) is associated with increased 20-HETE synthesis (113). CYP hydroxylase inhibitors attenuate the rat proximal tubule cell proliferative response to EGF (1). Signal transduction pathways were evaluated in a well-characterized porcine proximal tubule cell line, LLC-PK1.…”

Section: Proximal Tubular Transportmentioning

confidence: 99%

“…Signal transduction pathways were evaluated in a well-characterized porcine proximal tubule cell line, LLC-PK1. 20-HETE and 20-HETE analogs activate the Raf/MEK/ERK and Akt pathways in LLC-PK1 cells (1). Activation of these pathways by 20-HETE was secondary to the activation of c-Src and EGF receptor (1).…”

Section: Proximal Tubular Transportmentioning

confidence: 99%

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

Imig

Khan

2015

Comprehensive Physiology

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Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function.

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

Cited by 45 publications

References 50 publications

G-ProteinβγSubunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

G-ProteinβγSubunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

20-HETE Activates the Transcription of Angiotensin-Converting Enzyme via Nuclear Factor- B Translocation and Promoter Binding

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

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