title: Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions.
abstract: Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury. We evaluated the role of ERK1/2 on the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene, a master regulator of mitochondrial function. The potent and specific MEK1/2 inhibitor trametinib rapidly blocked ERK1/2 phosphorylation, decreased cytosolic and nuclear FOXO3a/1 phosphorylation, and increased PGC-1α gene expression and its downstream mitochondrial biogenesis (MB) targets under physiological conditions in the kidney cortex and in primary renal cell cultures. The epidermal growth factor receptor (EGFR) inhibitor erlotinib blocked ERK1/2 phosphorylation and increased PGC-1α gene expression similar to treatment with trametinib, linking EGFR activation and FOXO3a/1 inactivation to the down-regulation of PGC-1α and MB through ERK1/2. Pretreatment with trametinib blocked early ERK1/2 phosphorylation following ischemia/reperfusion kidney injury and attenuated the down-regulation of PGC-1α and downstream target genes. These results demonstrate that ERK1/2 rapidly regulates mitochondrial function through a novel pathway, EGFR/ERK1/2/FOXO3a/1/PGC-1α, under physiological and pathological conditions. As such, ERK1/2 down-regulates mitochondrial function directly by phosphorylation of upstream regulators of PGC-1α and subsequently decreasing MB.
authors.affiliation: From the Departments of Drug Discovery and Biomedical Sciences and.
authors.forename: Justin B
authors.initials: JB
authors.lastname: Collier
authors.affiliation: From the Departments of Drug Discovery and Biomedical Sciences and.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Whitaker
authors.affiliation: Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425 and.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Eblen
authors.affiliation: From the Departments of Drug Discovery and Biomedical Sciences and schnell@pharmacy.arizona.edu.|the Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina 29425.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011817:Rabbits; D015427:Reperfusion Injury / Q000150:complications* / Q000503:physiopathology*; D015398:Signal Transduction
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: FOXO; acute kidney injury (AKI); epidermal growth factor receptor (EGFR); extracellular signal-regulated kinase (ERK); ischemia reperfusion (IR); kidney; mitochondria