1. Academic Validation
  2. FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury

FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury

  • Redox Biol. 2024 Aug:74:103225. doi: 10.1016/j.redox.2024.103225.
Xiaolong Li 1 Feifei Yuan 1 Yabing Xiong 1 Ying Tang 2 Zhiru Li 1 Jun Ai 1 Jinhua Miao 1 Wenting Ye 1 Shan Zhou 1 Qinyu Wu 1 Xiaoxu Wang 1 Dan Xu 1 Jiemei Li 1 Jiewu Huang 1 Qiurong Chen 1 Weiwei Shen 1 Youhua Liu 1 Fan Fan Hou 1 Lili Zhou 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2 Department of Nephrology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 3 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: jinli730@smu.edu.cn.
Abstract

Acute kidney injury (AKI) is in high prevalence worldwide but with no therapeutic strategies. Programmed cell death in tubular epithelial cells has been reported to accelerate a variety of AKI, but the major pathways and underlying mechanisms are not defined. Herein, we identified that Pyroptosis was responsible for AKI progression and related to ATP depletion in renal tubular cells. We found that FAM3A, a mitochondrial protein that assists ATP synthesis, was decreased and negatively correlated with tubular cell injury and Pyroptosis in both mice and patients with AKI. Knockout of FAM3A worsened kidney function decline, increased macrophage and neutrophil cell infiltration, and facilitated tubular cell Pyroptosis in ischemia/reperfusion injury model. Conversely, FAM3A overexpression alleviated tubular cell Pyroptosis, and inhibited kidney injury in ischemic AKI. Mechanistically, FAM3A promoted PI3K/Akt/NRF2 signaling, thus blocking mitochondrial Reactive Oxygen Species (mt-ROS) accumulation. NLRP3 inflammasome sensed the overload of mt-ROS and then activated Caspase-1, which cleaved GSDMD, pro-IL-1β, and pro-IL-18 into their mature forms to mediate Pyroptosis. Of interest, NRF2 activator alleviated the pro-pyroptotic effects of FAM3A depletion, whereas the deletion of NRF2 blocked the anti-pyroptotic function of FAM3A. Thus, our study provides new mechanisms for AKI progression and demonstrates that FAM3A is a potential therapeutic target for treating AKI.

Keywords

AKI; FAM3A; Mitochondria; NRF2; Pyroptosis.

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