Augmenter of Liver Regeneration (ALR) Protects Kidney from Ischemia/Reperfusion (I/R) Injury via Regulation of TLR4/MAPK Signaling Pathway

Abstract

Toll-like receptor 4 (TLR4) can mediate innate activation and inflammation, and it is typically expressed within the ischemic kidney. Augmenter of liver regeneration (ALR) acts as an immunoregulator with a high expression in the kidney induced by renal ischemia/reperfusion (I/R) injury. Exogenous ALR has indicated a role in protecting the kidney from I/R injury. The protective effect of ALR is due to the immune regulatory function which remains to be elucidated. In this study, rats induced by renal I/R were treated with recombinant human ALR (rhALR) and demonstrated that the animals were protected from kidney I/R injury, implying that the rhALR-treated rats had less tubular damage than those untreated rats. Meanwhile, tubular epithelial cell apoptosis, neutrophil (24 h) and macrophage (72 h) infiltration to tubulointerstitium, and levels of inflammatory cytokines were decreased considerably in the rhALR-treated rats as compared to control. Additionally, rhALR could downregulate mRNA expression of TLR4 endogenous ligands and restrain its activation in renal I/R injury rats. It has also been proved that anti-rhALR antibody blocked the inhibition of rhALR of the immune inflammatory response in hypoxia/reoxygenation (H/R) injury in vitro. In rhALR+anti-rhALR antibody-intervened H/R cells, the expression of inflammatory cytokines was upregulated compared with the rhALR-treated cells. Taken together, rhALR could regulate the TLR4 signaling pathway to relieve inflammatory response, thereby protecting renal I/R injury, indicating that ALR is likely to be introduced to develop novel immune therapies for renal I/R injury.

Augmenter of liver regeneration knockout aggravates tubular ferroptosis and macrophage activation by regulating carnitine palmitoyltransferase‐1A‐induced lipid metabolism in diabetic nephropathy

“…augmenter of liver regeneration, carnitine palmitoyltransferase-1A, diabetic nephropathy, ferroptosis, lipid droplet-mitochondrial coupling, macrophage activation, mitochondria ferroptosis. 27 Intriguingly, Li et al 28 reported that ALR acts as an immunoregulator in the kidney after the induction of its high expression by renal I/R injury, and it decreases the infiltration of macrophage and the existence of inflammatory cytokines in I/R injury cell models through the TLR4/MAPK signaling pathway. These results imply that ALR could be a potential regulator of ferroptosis and macrophage activation in DN.…”