HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury

Aug 24, 2020Redox biology

Removal of damaged mitochondria in kidney tubule cells helps protect against kidney injury from limited blood flow

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Abstract

HIF-1α knockout significantly inhibited mitophagy and increased kidney damage in a mouse model of ischemia/reperfusion injury.

HIF-1α-mediated mitophagy may protect against acute kidney injury by reducing apoptosis and reactive oxygen species production.
Without HIF-1α, hypoxia/reoxygenation conditions led to decreased mitophagy and increased apoptosis in human tubular cells.
Overexpression of BNIP3 reversed the negative effects of HIF-1α knockout on mitophagy and kidney damage.
In vivo findings showed that loss of tubular HIF-1α resulted in greater kidney injury following ischemia/reperfusion.
BNIP3 appears to play a critical role in promoting mitophagy in conditions of HIF-1α deficiency.

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In the present study, we hypothesized that hypoxia-inducible factor 1α (HIF-1α)-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-1α 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 19-kDa interacting protein 3 (BNIP3), a downstream regulator of HIF-1α. Notably, BNIP3 overexpression reversed the inhibitory effect of HIF-1α knockout on H/R-induced mitophagy, and prevented the enhancing effect of HIF-1α knockout on H/R-induced apoptosis and ROS production. For in vivo study, we established HIF-1α; cadherin-16-cre mice in which tubular HIF-1α was specifically knockout. It was found that tubular HIF-1α 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-1α knockout mice with I/R injury. In summary, our study demonstrated that HIF-1α-BNIP3-mediated mitophagy in tubular cells plays a protective role through inhibition of apoptosis and ROS production in acute kidney damage. flox/flox

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HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury

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