Although disruption of mitochondrial homeostasis and biogenesis (MB) is a widely accepted pathophysiological feature of sepsis-induced 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. Down-regulation of PGC-1α, a master regulator of MB, was noted at the mRNA level at 3 h and protein level at 18 h in the renal cortex and was associated with loss of renal function following LPS treatment. LPS-mediated suppression of PGC-1α led to reduced expression of downstream regulators of MB and electron transport chain (ETC) proteins along with a reduction in renal cortical mitochondrial DNA content. Mechanistically, TLR4 knockout mice were protected from renal injury and disruption of MB after LPS. Immunoblot analysis revealed activation of TPL-2/MEK/ERK signaling in the renal cortex by LPS. Pharmacological inhibition of MEK/ERK signaling attenuated renal dysfunction and loss of PGC-1α, and was associated with a reduction in pro-inflammatory cytokine (e.g. TNF-α, IL-1β) expression at 3 h post-LPS. Neutralization of TNF-α also blocked PGC-1α suppression, but not renal dysfunction, following LPS-induced AKI. Finally, systemic administration of recombinant TNF-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.
- The American Society for Pharmacology and Experimental Therapeutics