The Role of Autophagy in Kidney Inflammatory Injury via the NF-κB Route Induced by LPS

Abstract

Acute kidney injury (AKI) is a systemic inflammatory response syndrome associated with poor clinical outcomes. No treatments effective for AKI are currently available. Thus, there is an urgent need of development of treatments effective for AKI. Autophagy, an intracellular proteolytic system, is induced in renal cells during AKI. However, whether autophagy is protective or injurious for AKI needs to be clearly clarified. We addressed this question by pharmacological inhibition of autophagy using a mouse model of lipopolysaccharide (LPS) induced-AKI. We found that autophagy was induced in renal cortex of mice during LPS-induced AKI as reflected by a dose-and time-dependent increased accumulation of light chain 3-II (LC3-II), the common marker of autophagy, compared to that of control group; 2) the occurrence of intensive, punctate and increased immunohistochemical staining image of LC3-II in renal cortex; 3) the significant increase in the expression levels of Beclin-1, another key marker of autophagy; 4) the significantly increased levels of plasma urea and serum creatinine and 5) the significant increase in autophagagosome area ratio. We observed that 3-methyladenine (3-MA), a pharmacological inhibitor of autophagy, blocked autophagy flux, alleviated AKI and protected against LPS-induced AKI. LPS triggered kidney inflammation by activation of the canonical NF-κB pathway. This route can be modulated by autophagy. Activation of the canonical NF-κB pathway was reduced in 3-MA+LPS as compared to that in LPS-treated group of mice. Mice pretreated with 3-MA before exposure to LPS showed a reduction in p65 phosphorylation, resulting in the accumulation of ubiquitinated IκB. In conclusion, impairment of autophagy ameliorates LPS-induced inflammation and decreases kidney injury. The accumulation of ubiquitinated IκB may be responsible for this effect.

The combination of lipopolysaccharide and D-galactosamine administration show positive genotoxic effect in mice liver

“…These result suggested that LPS/D-GalN activated a ROS-mediated toxic accumulation process in the brain after a long-term administration; however, exact molecular mechanism needs further investigation. Although liver is the major target for LPS insult, LPS-associated damages have been investigated in different organs, for instance, lung, heart and kidney [20][21][22]. Our present study conclude that the acute injection of LPS/D-GalN induces positive genotoxic effect only in liver cells, whilst the chronic injection of LPS/D-GalN induces positive genotoxic effect both in liver and brain cells.…”

Autophagy Induced FHL2 Upregulation Promotes IL-6 Production by Activating the NF-κB Pathway in Mouse Aortic Endothelial Cells after Exposure to PM2.5

“…Autophagy is required for hepatitis B virus X protein-induced NF-κB activation, and proinflammatory cytokine production [ 32 ]. Additionally, autophagy plays an important role in kidney related inflammatory injury via NF-κB activation induced by lipopolysaccharide [ 33 ], and in an early host antifungal response by enhancing NF-κB activity through A20 sequestration [ 34 ]. These findings suggest that autophagy might participate in the regulation of inflammatory factors by activating the NF-κB pathway.…”

Neutrophil pyroptosis: new perspectives on sepsis

“…Lipopolysaccharide is a major component of the cell wall of gram-negative bacteria. It can not only induce inflammation [61,68] and autophagy [62], but can also induce cell pyroptosis [13,[63][64][65]. Under the stimulation of intracellular LPS, Caspase-11 can specifically bind to the lipid A of LPS, which triggers Caspase-11 oligomerization, activates its proteolytic activity and cleaves the GSDMD to form a large number of pores on the cell membrane, eventually leading to membrane lysis and pyroptosis [13,63,64].…”