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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 352; no. 2; pp. 346 - 357
• Main Authors: Smith, Joshua A., Stallons, L. Jay, Collier, Justin B., Chavin, Kenneth D., Schnellmann, Rick G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - enzymology; Acute Kidney Injury - metabolism; Animals; Disease Models, Animal; DNA, Mitochondrial - metabolism; Dose-Response Relationship, Drug; Endotoxins - toxicity; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Gastrointestinal, Hepatic, Pulmonary, and Renal; Kidney Cortex - drug effects; Kidney Cortex - enzymology; Kidney Cortex - metabolism; Kidney Function Tests; Male; MAP Kinase Signaling System - drug effects; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; NGAL; PRC; NDUFB8; CLP; ATPSβ; LPS; KIM-1; NF-κB; MB; NRF-1; BUN; COX1; AKI; IL; KO; qRT-PCR; PGC-1β; PGC-1α; MAPK; TPL-2; MEK; TNF-α; TFAM; ND1; NDUFS1; TLR4; ERK
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.114.221085

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.