TY - JOUR
T1 - miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation
AU - Zhu, Jiefu
AU - Xiang, Xiaohong
AU - Hu, Xiaoru
AU - Li, Chenglong
AU - Song, Zhixia
AU - Dong, Zheng
N1 - Publisher Copyright:
© 2023 American Society of Nephrology. All rights reserved.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - Significance StatementCold storage-associated transplantation (CST) injury occurs in renal transplant from deceased donors, the main organ source. The pathogenesis of CST injury remains poorly understood, and effective therapies are not available. This study has demonstrated an important role of microRNAs in CST injury and revealed the changes in microRNA expression profiles. Specifically, microRNA-147 (miR-147) is consistently elevated during CST injury in mice and in dysfunctional renal grafts in humans. Mechanistically, NDUFA4 (a key component of mitochondrial respiration complex) is identified as a direct target of miR-147. By repressing NDUFA4, miR-147 induces mitochondrial damage and renal tubular cell death. Blockade of miR-147 and overexpression of NDUFA4 reduce CST injury and improve graft function, unveiling miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.BackgroundKidney injury due to cold storage-associated transplantation (CST) is a major factor determining the outcome of renal transplant, for which the role and regulation of microRNAs remain largely unclear.MethodsThe 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.ResultsKnockout 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.ConclusionsmicroRNAs, 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.
AB - Significance StatementCold storage-associated transplantation (CST) injury occurs in renal transplant from deceased donors, the main organ source. The pathogenesis of CST injury remains poorly understood, and effective therapies are not available. This study has demonstrated an important role of microRNAs in CST injury and revealed the changes in microRNA expression profiles. Specifically, microRNA-147 (miR-147) is consistently elevated during CST injury in mice and in dysfunctional renal grafts in humans. Mechanistically, NDUFA4 (a key component of mitochondrial respiration complex) is identified as a direct target of miR-147. By repressing NDUFA4, miR-147 induces mitochondrial damage and renal tubular cell death. Blockade of miR-147 and overexpression of NDUFA4 reduce CST injury and improve graft function, unveiling miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.BackgroundKidney injury due to cold storage-associated transplantation (CST) is a major factor determining the outcome of renal transplant, for which the role and regulation of microRNAs remain largely unclear.MethodsThe 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.ResultsKnockout 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.ConclusionsmicroRNAs, 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.
KW - NDUFA4
KW - cold storage
KW - kidney transplantation
KW - microRNA
KW - mitochondria
KW - proximal tubular cells
UR - http://www.scopus.com/inward/record.url?scp=85164907919&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85164907919&partnerID=8YFLogxK
U2 - 10.1681/ASN.0000000000000154
DO - 10.1681/ASN.0000000000000154
M3 - Article
C2 - 37211637
AN - SCOPUS:85164907919
SN - 1046-6673
VL - 34
SP - 1381
EP - 1397
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 8
ER -