HIF-1a-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury
ZJ Fu, etc
Redox Biology,
2020
In the present study, we hypothesized that hypoxia-inducible factor 1a (HIF-1a)-mediated mitophagy plays a protective role in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Mitophagy was evaluated by measuring the changes of mitophagy flux, mitochondria DNA copy number, and the changes of mitophagy-related proteins including translocase of outer mitochondrial membrane 20 (TOMM20), cytochrome c oxidase IV (COX IV), microtubule-associated protein 1 light chain 3B (LC3B), and mitochondria adaptor nucleoporin p62 in HK2 cells, a human tubular cell line. Results show that HIF-1a knockout significantly attenuated hypoxia/reoxygenation (H/R)-induced mitophagy, aggravated H/R-induced apoptosis, and increased the production of reactive oxygen species (ROS). Similarly, H/R induced significantly increase in Bcl-2 nineteen-kilodalton interacting protein 3 (BNIP3), a downstream regulator of HIF-1a. Notably, BNIP3 overexpression reversed the inhibitory effect of HIF-1a knockout on H/R-induced mitophagy, and prevented the enhancing effect of HIF-1a knockout on H/R-induced apoptosis and ROS production. For in vivo study, we established HIF-1aflox/flox; cadherin-16-cre mice in which tubular HIF-1a was specifically knockout. It was found that tubular HIF-1a knockout significantly inhibited I/R-induced mitophagy, and aggravated I/R-induced tubular apoptosis and kidney damage. In contrast, adenovirus-mediated BNIP3 overexpression significantly reversed the decreased mitophagy, and prevented enhanced kidney damage in tubular HIF-1a knockout mice with I/R injury. In summary, our study demonstrated that HIF-1a-BNIP3-mediated mitophagy in tubular cells plays a protective role through inhibition of apoptosis and ROS production in acute kidney damage.
- Journal
- Redox Biology
- Year
- 2020
- Page
- doi: 10.1016/j.redox.2020.101671
- Institute
- Shanghai Jiao Tong University
Referenced Products
Product | Cat No. |
---|---|
Ad-m-BNIP3 | ADV-254045 |
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