The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential
Abstract
:1. Introduction
2. An Overview of AKI and CKD as Well as AKI to CKD Transition
3. An Overview of Mitochondrial Structure, Biogenesis, and Dynamics
3.1. Mitochondrial Structure
3.2. Mitochondrial Dynamics
3.3. Mitochondrial Biogenesis
4. The Roles of Mitochondrial in AKI, CKD, and AKI to CKD Transition
4.1. The Roles of Mitochondrial Structure, Dynamics, and Biogenesis in AKI
4.2. The Roles of Mitochondrial Dynamics and Biogenesis in CKD
4.3. The Roles of Mitochondrial Dysfunction and Its Crosstalk with ER in the Transition of AKI to CKD
5. Mitochondrial Oxidative Stress in AKI and CKD
6. Mitochondrial Targeting for AKI and CKD Therapy
6.1. Cardiolipin Protection Agents
6.2. Modulating Mitochondrial Dynamics
6.3. Altering Mitochondrial Biogenesis
6.4. Altering Mitochondrial Biogenesis
6.5. mPTP Inhibitors
6.6. Mitochondrial-Targeted Antioxidants
7. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Therapeutics | Mechanism(s) of Action | Experimental Model | Clinical Trial | References |
---|---|---|---|---|
Cardiolipin protection | ||||
SS-31 | Binds to cardiolipin, prevents peroxidase activity and improves mitochondrial respiration and ATP production; Inhibits cytochrome c release; Normalizes mitochondrial potential (ΔΨm) | IRI-AKI, UUO, and DKD | Mitochondrial myopathy (NCT02367014) Age-related skeletal muscle mitochondrial dysfunction (NCT02245620) | [80,96,97,98] |
SS-20 | Reduces mitochondrial matrix swelling and preserves cristae membranes; Increases ATP and reduces ROS | IRI-AKI | [99] | |
Fission inhibitor | ||||
Mdivi-1 | Selectively inhibits Drp1; Induces mitochondria fusion and increases ATP production | IRI-AKI, ADPKD, and UUO | [100,101,102] | |
Biogenesis activator | ||||
SRT1720 | Sirt-1 activator; Restores renal expression of PGC-1α, mitochondrial mass, ATP levels | IRI-AKI and UUO | [103,104] | |
Resveratrol | Sirt-1 activator; Restores mitochondrial respiratory capacity and decreases the production of mtROS and lipid peroxidation | Hemorrhagic shock induces AKI and db/db mice | [20,71,105,106,107] | |
AICAR | AMPK activator; Attenuates nitrosative stress and monocyte/macrophage infiltration | IRI-AKI and UUO | [13,108,109] | |
Formoterol | Agonist of β2-adrenoreceptor, increase PGC-1α synthesis and induces mitochondrial biogenesis by increasing mtDNA copy numbers, oxygen consumption rate | IRI-AKI and db/db mice | [110,111,112] | |
Fenofibrate/Bezafibrate | Peroxisomal proliferator-activated receptor (PPAR)-α agonist, lipid lowering, increases mitochondrial biogenesis | CKD and DKD | Diabetic complications (CVD and DKD) (FIELD, ISRCTN 64783481) | [113] |
mPTP inhibitor | ||||
CSA | Interacts with cyclophilin D; Suppresses mPTP opening and mitochondria swelling | IRI-AKI | Acute myocardial infarction (NCT01595958) Severe traumatic brain injury (NCT01825044) | [114] |
TDZD-8 | Selectively inhibits GSK-3β; Diminishes MPT | Drug-induced AKI and IRI-AKI | [115,116,117] | |
Antioxidants | ||||
CoQ10 | Normalizes ATP production, attenuates mtROS and decreases mitochondrial ΔΨm | db/db mice | Mitochondrial disorders (NCT00432744) Parkinson disease (NCT00740714) | [118] |
MitoQ | ROS scavenger; Antioxidant concentrates at matrix in a ΔΨm-dependent manner | IRI-AKI Ins2(+/)⁻(AkitaJ) mice | Parkinson’s disease (NCT00329056) Fatty acid disease (NCT01167088) Hepatitis C (NCT00433108) CKD (NCT02364648) | [66,119] |
SkQR1 | Antioxidant and decreased mitochondrial ΔΨm | IRI-AKI and gentamycin-induced renal failure | [120,121]. | |
Curcumin | Antioxidant; Alteration of mitochondrial dynamics and bioenergetics. | 5/6NX mice and db/db mice | Leber hereditary optic neuropathy (NCT00528151) | [122,123,124] |
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Zhang, X.; Agborbesong, E.; Li, X. The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential. Int. J. Mol. Sci. 2021, 22, 11253. https://doi.org/10.3390/ijms222011253
Zhang X, Agborbesong E, Li X. The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential. International Journal of Molecular Sciences. 2021; 22(20):11253. https://doi.org/10.3390/ijms222011253
Chicago/Turabian StyleZhang, Xiaoqin, Ewud Agborbesong, and Xiaogang Li. 2021. "The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential" International Journal of Molecular Sciences 22, no. 20: 11253. https://doi.org/10.3390/ijms222011253