Li Lu'an, Zhang Li, Cai Yating, Li Jiaying, Zheng Siqi, Wang Weiteng, Chen Yinwen, Luo Jieyi, Li Ruizhao, Liang Xinling
School of Medicine, South China University of Technology, Guangzhou, China.
Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Front Cell Dev Biol. 2024 Nov 26;12:1457369. doi: 10.3389/fcell.2024.1457369. eCollection 2024.
Pyroptosis is one of the ways to cause proximal tubular epithelial cell death in diabetic nephropathy (DN), but the exact mechanism remains unclear. Absent in melanoma 2 (AIM2), a sensor for double-stranded DNA, creates an inflammasome that triggers the cleavage of gasdermin D (GSDMD), leading to a type of inflammatory cell death called pyroptosis. This study investigated the role of AIM2 in pyroptosis within proximal tubular epithelial cells in DN. We observed significantly elevated AIM2 expression in renal tubules from DN patients and db/db mice, as well as in high glucose (HG)-induced Human Kidney-2 (HK2) cells. Besides, increased AIM2 expression was accompanied by activation of the pyroptosis pathway (cleaved-caspase-1, GSDMD-FL, GSDMD-NT) in the renal cortex of db/db mice and HG-induced HK2 cells . Knocking down GSDMD can reduce HG-induced HK2 cell death, indicating that HG triggers pyroptosis in HK2 cells. Furthermore, HG-induced pyroptosis was mitigated in HK2 cells with AIM2 knockdown using siRNA. Additionally, reducing ROS levels using NAC was able to attenuate HG-induced HK2 cells DNA damage, AIM2 activation, and pyroptosis. Notably, AIM2 upregulation was observed in renal biopsies from DN patients, with expression levels positively correlating with serum creatinine and inversely with estimated glomerular filtration rate (eGFR). Collectively, DNA damage caused by HG could result in the activation of the AIM2 inflammasome, leading to the pyroptosis of proximal tubular epithelial cells, indicating that targeting AIM2 could be a potential novel approach for treating DN.
细胞焦亡是糖尿病肾病（DN）中导致近端肾小管上皮细胞死亡的方式之一，但其确切机制仍不清楚。黑色素瘤缺乏因子2（AIM2）是一种双链DNA传感器，可形成炎性小体，触发gasdermin D（GSDMD）的裂解，导致一种称为细胞焦亡的炎性细胞死亡。本研究探讨了AIM2在DN近端肾小管上皮细胞焦亡中的作用。我们观察到，DN患者和db/db小鼠肾小管中以及高糖（HG）诱导的人肾2（HK2）细胞中AIM2表达显著升高。此外，db/db小鼠肾皮质和HG诱导的HK2细胞中，AIM2表达增加伴随着细胞焦亡途径（裂解的半胱天冬酶-1、GSDMD-FL、GSDMD-NT）的激活。敲低GSDMD可减少HG诱导的HK2细胞死亡，表明HG触发HK2细胞焦亡。此外，使用小干扰RNA敲低AIM2的HK2细胞中，HG诱导的细胞焦亡得到缓解。此外，使用NAC降低活性氧水平能够减轻HG诱导的HK2细胞DNA损伤、AIM2激活和细胞焦亡。值得注意的是，在DN患者的肾活检中观察到AIM2上调，其表达水平与血清肌酐呈正相关，与估计肾小球滤过率（eGFR）呈负相关。总之，HG引起的DNA损伤可导致AIM2炎性小体激活，导致近端肾小管上皮细胞焦亡，表明靶向AIM2可能是治疗DN的一种潜在新方法。
