Allicin Attenuates Sepsis‐Induced Acute Kidney Injury by Inhibiting Pyroptosis Through Negative Regulation of the PI3K/AKT Pathway

Pyroptosis is a critical mechanism leading to sepsis-induced acute kidney injury (S-AKI). Allicin, an organosulfur compound extracted from garlic bulbs, protects against S-AKI through its anti-pyroptotic role, but the underlying pathophysiological mechanisms remain largely unknown. In in vivo and in vitro experiments, rats and HK-2 cells were induced by caecal ligation and puncture (CLP) and lipopolysaccharides (LPSs), respectively. They were then treated with allicin, insulin-like growth factor-1 (IGF-1, a PI3K/AKT agonist), or both. In this study, we found that the levels of p-PI3K, p-AKT, NF-κB, NLRP3, caspase-1, gasdermin D (GSDMD)-N, IL-1β, IL-18 and lactate dehydrogenase (LDH) were significantly increased, which was accompanied by kidney tissue and HK-2 cell pyroptosis, eventually leading to elevated serum creatinine (Scr) and blood urea nitrogen (BUN) levels, increased 7-day mortality and reduced HK-2 cell activity in CLP-induced rats and LPS-induced HK-2 cells, respectively. Moreover, we observed that allicin significantly reduced the levels of p-PI3K, p-AKT, NF-κB, NLRP3, caspase-1, GSDMD-N, IL-1β, IL-18 and LDH and inhibited pyroptosis in renal tissues and HK-2 cells, ultimately resulting in improved kidney function, 7-day survival, and enhanced HK-2 cell activity in CLP-induced rats and LPS-induced HK-2 cells. Furthermore, our results demonstrate that agonism of the PI3K/AKT pathway-by using IGF-1-could reverse the abovementioned protective role of allicin, accompanied by increased phosphorylation of PI3K and AKT in vivo and in vitro. Overall, the findings of this study demonstrate that the protective effect of allicin on S-AKI is largely dependent on the inhibition of pyroptosis through the negative regulation of the PI3K/AKT pathway.