title: Suppression of mitochondrial biogenesis through toll-like receptor 4-dependent mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling in endotoxin-induced acute kidney injury.
abstract: Although disruption of mitochondrial homeostasis and biogenesis (MB) is a widely accepted pathophysiologic feature of sepsis-induced acute kidney injury (AKI), the molecular mechanisms responsible for this phenomenon are unknown. In this study, we examined the signaling pathways responsible for the suppression of MB in a mouse model of lipopolysaccharide (LPS)-induced AKI. Downregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of MB, was noted at the mRNA level at 3 hours and protein level at 18 hours in the renal cortex, and was associated with loss of renal function after LPS treatment. LPS-mediated suppression of PGC-1α led to reduced expression of downstream regulators of MB and electron transport chain proteins along with a reduction in renal cortical mitochondrial DNA content. Mechanistically, Toll-like receptor 4 (TLR4) knockout mice were protected from renal injury and disruption of MB after LPS exposure. Immunoblot analysis revealed activation of tumor progression locus 2/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (TPL-2/MEK/ERK) signaling in the renal cortex by LPS. Pharmacologic inhibition of MEK/ERK signaling attenuated renal dysfunction and loss of PGC-1α, and was associated with a reduction in proinflammatory cytokine (e.g., tumor necrosis factor-α [TNF-α], interleukin-1β) expression at 3 hours after LPS exposure. Neutralization of TNF-α also blocked PGC-1α suppression, but not renal dysfunction, after LPS-induced AKI. Finally, systemic administration of recombinant tumor necrosis factor-α alone was sufficient to produce AKI and disrupt mitochondrial homeostasis. These findings indicate an important role for the TLR4/MEK/ERK pathway in both LPS-induced renal dysfunction and suppression of MB. TLR4/MEK/ERK/TNF-α signaling may represent a novel therapeutic target to prevent mitochondrial dysfunction and AKI produced by sepsis.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences (J.A.S., L.J.S., J.B.C., R.G.S.) and Division of Transplant Surgery, Department of Surgery (K.D.C.), Medical University of South Carolina, Charleston, South Carolina ; and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Department of Drug Discovery and Biomedical Sciences (J.A.S., L.J.S., J.B.C., R.G.S.) and Division of Transplant Surgery, Department of Surgery (K.D.C.), Medical University of South Carolina, Charleston, South Carolina ; and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: L Jay
authors.initials: LJ
authors.lastname: Stallons
authors.affiliation: Department of Drug Discovery and Biomedical Sciences (J.A.S., L.J.S., J.B.C., R.G.S.) and Division of Transplant Surgery, Department of Surgery (K.D.C.), Medical University of South Carolina, Charleston, South Carolina ; and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Justin B
authors.initials: JB
authors.lastname: Collier
authors.affiliation: Department of Drug Discovery and Biomedical Sciences (J.A.S., L.J.S., J.B.C., R.G.S.) and Division of Transplant Surgery, Department of Surgery (K.D.C.), Medical University of South Carolina, Charleston, South Carolina ; and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Chavin
authors.affiliation: Department of Drug Discovery and Biomedical Sciences (J.A.S., L.J.S., J.B.C., R.G.S.) and Division of Transplant Surgery, Department of Surgery (K.D.C.), Medical University of South Carolina, Charleston, South Carolina ; and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.) schnell@musc.edu.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007677:Kidney Function Tests; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D004731:Endotoxins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; C044101:endotoxin, Escherichia coli; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases