miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation

作者：Zhu, Jiefu; Xiang, Xiaohong; Hu, Xiaoru; Li, Chenglong; Song, Zhixia^*; Dong, Zheng^*

来源：Journal of the American Society of Nephrology : JASN , 2023, 34(8): 1381-1397.

DOI：10.1681/ASN.0000000000000154

• ISCHEMIA-REPERFUSION INJURY
• CYTOCHROME-C-OXIDASE
• PROXIMAL TUBULE
• MICRORNAS
• PROGRESSION
• ACTIVATION
• INDUCTION
• REJECTION
• SUBUNIT
• TARGET

Background Kidney injury due to cold storage-associated transplantation (CST) is amajor factor determining the outcome of renal transplant, for which the role and regulation of microRNAs remain largely unclear. @@@ Methods The kidneys of proximal tubule Dicer (an enzyme for microRNA biogenesis) knockout mice and their wild-type littermates were subjected to CST to determine the function of microRNAs. Small RNA sequencing then profiled microRNA expression in mouse kidneys after CST. Anti-microRNA-147 (miR-147) and miR-147 mimic were used to examine the role of miR- 147 in CST injury in mouse and renal tubular cell models. @@@ Results Knockout of Dicer from proximal tubules attenuated CST kidney injury in mice. RNA sequencing identified multiple microRNAs with differential expression in CST kidneys, among which miR-147 was induced consistently in mouse kidney transplants and in dysfunctional human kidney grafts. Anti-miR-147 protected against CST injury in mice and ameliorated mitochondrial dysfunction after ATP depletion injury in renal tubular cells in intro. Mechanistically, miR-147 was shown to target NDUFA4, a key component of the mitochondrial respiration complex. Silencing NDUFA4 aggravated renal tubular cell death, whereas overexpression of NDUFA4 prevented miR-147-induced cell death and mitochondrial dysfunction. Moreover, overexpression of NDUFA4 alleviated CST injury in mice. @@@ Conclusions microRNAs, as a class of molecules, are pathogenic in CST injury and graft dysfunction. Specifically, miR-147 induced during CST represses NDUFA4, leading to mitochondrial damage and renal tubular cell death. These results unveil miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.

• 单位
  1; 武汉大学