Abstract
Renal ischemia-reperfusion injury is a leading cause of acute kidney injury; the pathogenesis of which remains poorly understood and effective therapies are still lacking. Here we tested whether microRNAs, identified as critical regulators of cell health and disease, are involved in this process. We found that miR-17-5p was significantly up-regulated during renal ischemia-reperfusion injury in mice and during hypoxia in cultured renal tubular cells. In cultured cells, miR-17-5p directly inhibited the expression of death receptor 6 (DR6) and attenuated apoptosis during hypoxia. Blockade of miR-17-5p abolished the suppression of DR6 and facilitated caspase activation and apoptosis. In vivo, an miR-17-5p mimic suppressed DR6 expression and protected against renal ischemia-reperfusion injury. We further verified that miR-17-5p induction during renal ischemia-reperfusion injury was dependent on p53. Inhibition of p53 with pifithrin-α or a dominant-negative mutant led to the repression of miR-17-5p expression under hypoxia in vitro. Moreover, miR-17-5p induction during renal ischemia-reperfusion injury was attenuated in proximal tubule p53 knockout mice, supporting the role of p53 in miR-17-5p induction in vivo. Thus, p53/miR-17-5p/DR6 is a new protective pathway in renal ischemia-reperfusion injury and may be targeted for the prevention and treatment of ischemic acute kidney injury.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 106-118 |
| Number of pages | 13 |
| Journal | Kidney International |
| Volume | 91 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2017 |
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Keywords
- acute kidney injury
- death receptor
- ischemia-reperfusion injury
- microRNA
ASJC Scopus subject areas
- Nephrology
Cite this
Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor 6. / Hao, Jielu; Wei, QingQing; Mei, Shuqin; Li, Lin; Su, Yunchao; Mei, Changlin; Dong, Zheng.
In: Kidney International, Vol. 91, No. 1, 01.01.2017, p. 106-118.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor 6
AU - Hao, Jielu
AU - Wei, QingQing
AU - Mei, Shuqin
AU - Li, Lin
AU - Su, Yunchao
AU - Mei, Changlin
AU - Dong, Zheng
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Renal ischemia-reperfusion injury is a leading cause of acute kidney injury; the pathogenesis of which remains poorly understood and effective therapies are still lacking. Here we tested whether microRNAs, identified as critical regulators of cell health and disease, are involved in this process. We found that miR-17-5p was significantly up-regulated during renal ischemia-reperfusion injury in mice and during hypoxia in cultured renal tubular cells. In cultured cells, miR-17-5p directly inhibited the expression of death receptor 6 (DR6) and attenuated apoptosis during hypoxia. Blockade of miR-17-5p abolished the suppression of DR6 and facilitated caspase activation and apoptosis. In vivo, an miR-17-5p mimic suppressed DR6 expression and protected against renal ischemia-reperfusion injury. We further verified that miR-17-5p induction during renal ischemia-reperfusion injury was dependent on p53. Inhibition of p53 with pifithrin-α or a dominant-negative mutant led to the repression of miR-17-5p expression under hypoxia in vitro. Moreover, miR-17-5p induction during renal ischemia-reperfusion injury was attenuated in proximal tubule p53 knockout mice, supporting the role of p53 in miR-17-5p induction in vivo. Thus, p53/miR-17-5p/DR6 is a new protective pathway in renal ischemia-reperfusion injury and may be targeted for the prevention and treatment of ischemic acute kidney injury.
AB - Renal ischemia-reperfusion injury is a leading cause of acute kidney injury; the pathogenesis of which remains poorly understood and effective therapies are still lacking. Here we tested whether microRNAs, identified as critical regulators of cell health and disease, are involved in this process. We found that miR-17-5p was significantly up-regulated during renal ischemia-reperfusion injury in mice and during hypoxia in cultured renal tubular cells. In cultured cells, miR-17-5p directly inhibited the expression of death receptor 6 (DR6) and attenuated apoptosis during hypoxia. Blockade of miR-17-5p abolished the suppression of DR6 and facilitated caspase activation and apoptosis. In vivo, an miR-17-5p mimic suppressed DR6 expression and protected against renal ischemia-reperfusion injury. We further verified that miR-17-5p induction during renal ischemia-reperfusion injury was dependent on p53. Inhibition of p53 with pifithrin-α or a dominant-negative mutant led to the repression of miR-17-5p expression under hypoxia in vitro. Moreover, miR-17-5p induction during renal ischemia-reperfusion injury was attenuated in proximal tubule p53 knockout mice, supporting the role of p53 in miR-17-5p induction in vivo. Thus, p53/miR-17-5p/DR6 is a new protective pathway in renal ischemia-reperfusion injury and may be targeted for the prevention and treatment of ischemic acute kidney injury.
KW - acute kidney injury
KW - death receptor
KW - ischemia-reperfusion injury
KW - microRNA
UR - http://www.scopus.com/inward/record.url?scp=84995444911&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84995444911&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2016.07.017
DO - 10.1016/j.kint.2016.07.017
M3 - Article
C2 - 27622990
AN - SCOPUS:84995444911
VL - 91
SP - 106
EP - 118
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 1
ER -