Rapamycin induces autophagy to alleviate acute kidney injury following cerebral ischemia and reperfusion via the mTORC1/ATG13/ULK1 signaling pathway

Abstract

Acute kidney injury (AKI) is a clinically common and severe complication of ischemia-reperfusion (I/R), associated with high morbidity and mortality rates, and prolonged hospitalization. Rapamycin is a type of macrolide, primarily used for anti-rejection therapy following organ transplantation and the treatment of autoimmune diseases. Rapamycin has been identified to exert a protective effect against AKI induced by renal I/R as an autophagy inducer. However, whether rapamycin preconditioning may relieve AKI following cerebral I/R (CIR) remains to be fully elucidated. The purpose of the present study was to investigate the effects of CIR on the renal system of rats and the role of rapamycin in AKI following CIR. In the present study, a CIR model was established in Sprague-Dawley rats via a 90-min period of middle cerebral artery occlusion and 24 h reperfusion, and pretreatment with an intraperitoneal injection of rapamycin (dosage: 1 mg/kg; 0.5 h) prior to CIR. The levels of serum creatinine and blood urea nitrogen (BUN), and the expression of inflammation-, apoptosis- and autophagy-associated markers were subsequently measured. In addition to certain histopathological alterations to the kidney, it was identified that CIR significantly increased the levels of serum creatinine, BUN, tumor necrosis factor-α and interleukin-1β, and significantly induced apoptosis and autophagy. It was observed that rapamycin induced autophagy through the mammalian target of rapamycin complex 1/autophagy-related 13/unc-51 like autophagy activating kinase 1 signaling pathway, and that rapamycin pre-treatment significantly improved renal function and alleviated renal tissue inflammation and cell apoptosis in rats following CIR. In conclusion, the results suggested that rapamycin may alleviate AKI following CIR via the induction of autophagy.

Deficiency of apoptosis‐stimulating protein two of p53 ameliorates acute kidney injury induced by ischemia reperfusion in mice through upregulation of autophagy

“…48 Su et al observed that renal tissue inflammation and cell apoptosis can be alleviated via the induction of autophagy in AKI following cerebral I/R rats. 49 Similar to previous findings, our results confirmed that the suppression of autophagy can deteriorate renal tubular injury induced by I/R, leading to renal insufficiency. Additionally, autophagy inhibition also promoted mRNA expression of inflammatory cytokines and renal cell apoptosis, suggesting that autophagy participated in the protective effects of renal injury.…”

Role of sirtuin-1 in diabetic nephropathy

“…Furthermore, both the AMPK and mTOR pathways regulate autophagy. AMPK is a positive regulator of autophagy, while the mTOR pathway is a negative regulator, activating or inhibiting UNC51-like kinase 1 complex, which is essential for the initiation of autophagy [104, 105]. Indeed, the impaired autophagy observed in DN is associated with defects in both the mTOR and AMPK pathways.…”

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…ULK1 is then able to activate this PI3K complex and promote autophagosome synthesis . Upon activation, mTORC1 promotes anabolic processes through phosphorylation of its eukaryotic translation initiation factor 4E binding protein and downstream effectors ribosomal protein S6 kinase, thereby inducing cell proliferation and growth . When growth factors/amino acids or energy are abundant, mTORC1 represses autophagic process through inhibitory phosphorylation of ATG13, which reduces the activity of a mTORC1 direct target, ULK1, thereby decreasing the rate of autophagosome formation …”

“…21 Upon activation, mTORC1 promotes anabolic processes through phosphorylation of its eukaryotic translation initiation factor 4E binding protein and downstream effectors ribosomal protein S6 kinase, thereby inducing cell proliferation and growth. 20,22 When growth factors/amino acids or energy are abundant, mTORC1 represses autophagic process through inhibitory phosphorylation of ATG13, which reduces the activity of a mTORC1 direct target, ULK1, thereby decreasing the rate of autophagosome formation. 21,23 Also, autophagy is not only a way for cells to gain nutrients by degrading cellular components during starvation but is also an important defense mechanism against intracellular pathogens.…”