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Technical Refinement of a Bilateral Renal Ischemia-Reperfusion Mouse Model for Acute Kidney Injury Research
Published on: November 3, 2023
Programmed cell death in acute kidney injury: From molecular mechanisms to targeted therapies
Bingyang Xu1, Yuanyuan Zheng2, Yao Hu3
1The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310052, PR China.
Abstract:
Acute kidney injury (AKI) represents a formidable global health challenge characterized by high morbidity and mortality, yet effective pharmacological interventions remain elusive. Programmed cell death (PCD) pathways, orchestrating the depletion of renal tubular epithelial cells, are increasingly recognized as central drivers of AKI pathogenesis. Despite the rapid expansion of PCD-targeted agents in other therapeutic areas, their translational potential in AKI has not been fully exploited. This review provides a systematic synthesis of the molecular mechanisms governing diverse PCD modalities in renal injury, including apoptosis, pyroptosis, necroptosis, ferroptosis, cuproptosis, cellular senescence, and PANoptosis. We comprehensively analyze the intricate regulatory networks of these pathways and highlight emerging therapeutic targets, including transmembrane protein 16A (TMEM16A), signal transducer and activator of transcription 3 (STAT3), glutathione peroxidase 4 (GPX4), and others. Furthermore, we evaluate the developmental status of promising investigational agents, ranging from small-molecule inhibitors and agonists to novel PROteolysis-TArgeting Chimera (PROTAC) degraders (e.g., targeting STAT3). By integrating recent mechanistic advances with preclinical pharmacological evidence, this review outlines a rational framework for developing precision therapeutics targeting PCD signaling nodes, paving the way for novel strategies to halt AKI progression and facilitate renal recovery.
Insights
Programmed cell death (PCD) pathways drive acute kidney injury (AKI). Targeting these diverse PCD modalities offers a promising strategy for developing novel AKI therapeutics and promoting renal recovery.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Acute kidney injury (AKI) is a major health concern with high mortality and limited treatments.
- Programmed cell death (PCD) pathways are key drivers of AKI by causing renal tubular epithelial cell loss.
- Existing PCD-targeted therapies are underexplored for AKI treatment.
Purpose of the Study:
- To systematically review the molecular mechanisms of various PCD modalities in renal injury.
- To identify emerging therapeutic targets within these PCD pathways.
- To evaluate the translational potential of investigational agents for AKI.
Main Methods:
- Comprehensive analysis of molecular mechanisms governing apoptosis, pyroptosis, necroptosis, ferroptosis, cuproptosis, senescence, and PANoptosis in AKI.
- Review of preclinical data on small-molecule inhibitors, agonists, and PROTAC degraders.
- Synthesis of recent mechanistic advances and pharmacological evidence.
Main Results:
- PCD pathways, including apoptosis, pyroptosis, necroptosis, ferroptosis, cuproptosis, senescence, and PANoptosis, are central to AKI pathogenesis.
- Emerging therapeutic targets like TMEM16A, STAT3, and GPX4 are identified.
- Investigational agents, including PROTACs targeting STAT3, show promise.
Conclusions:
- Targeting specific PCD signaling nodes offers a rational framework for precision AKI therapeutics.
- Developing novel strategies focused on PCD offers potential to halt AKI progression and improve renal recovery.
- Further research into PCD pathways is crucial for advancing AKI treatment.
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