Indispensable role of mitochondria in maintaining the therapeutic potential of curcumin in acute kidney injury.
Ling LiShuyun LiuYijie ZhouMeng ZhaoYizhuo WangChengshi WangPeng LouRongshuang HuangLiang MaYanrong LuPing FuJingping LiuPublished in: Journal of cellular and molecular medicine (2021)
Acute kidney injury (AKI) is a serious disease for which effective therapeutic agents are required. The capacity of curcumin (CUR) to resolve renal inflammation/oxidative stress and mitochondrial damage has been reported, but crosstalk between these effects and the consequence of this crosstalk remain elusive. In this study, a hypoxia/reoxygenation (H/R)-induced renal tubular epithelial cell (TEC) injury model and an ischaemia/reperfusion (I/R)-induced mouse AKI model were treated with CUR with or without mitochondrial inhibitors (rotenone and FCCP) or siRNA targeting mitochondrial transcription factor A (TFAM). Changes in mitochondrial function, inflammation, the antioxidant system and related pathways were analysed. In vitro, CUR suppressed NFκB activation and cytokine production and induced NRF2/HO-1 signalling in TECs under H/R conditions. CUR treatment also reduced mitochondrial ROS (mtROS) and mitochondrial fragmentation and enhanced mitochondrial biogenesis, TCA cycle activity and ATP synthesis in damaged TECs. However, the anti-inflammatory and antioxidant effects of CUR in damaged TECs were markedly abolished upon mitochondrial disruption. In vivo, CUR treatment improved renal function and antioxidant protein (NRF2 and SOD2) expression and reduced oxidative stress (8-OHdG), tubular apoptosis/death, cytokine release/macrophage infiltration and mitochondrial damage in the kidneys of AKI mice. In vitro, the anti-inflammatory and antioxidant effects of CUR in damaged kidneys were impaired when mitochondrial function was disrupted. These results suggest mitochondrial damage is a driving factor of renal inflammation and redox imbalance. The therapeutic capacity of CUR in kidneys with AKI is primarily dependent on mitochondrial mechanisms; thus, CUR is a potential therapy for various diseases characterized by mitochondrial damage.
Keyphrases
- oxidative stress
- diabetic rats
- acute kidney injury
- dna damage
- induced apoptosis
- ischemia reperfusion injury
- anti inflammatory
- transcription factor
- cardiac surgery
- high glucose
- signaling pathway
- heat shock
- cell death
- coronary artery disease
- immune response
- poor prognosis
- cell proliferation
- drug delivery
- long non coding rna
- cell cycle arrest
- reactive oxygen species
- risk assessment
- hyaluronic acid
- protein protein
- amino acid
- electron transfer
- brain injury
- newly diagnosed