Mechanisms of Acute Kidney Injury–Chronic Kidney Disease Transition: Unraveling Maladaptive Repair and Therapeutic Opportunities
Abstract
:1. Introduction
2. Renal Tubular Regeneration: Balancing Adaptive Repair and Maladaptive Responses
3. Mechanisms of Maladaptive Repair
3.1. Epigenetic Reprogramming
3.2. Cellular Senescence and G2/M Cell-Cycle Arrest
3.3. Mitochondrial Dysfunction and Metabolism Reprogramming
3.3.1. Mitochondrial Damage
3.3.2. Metabolism Reprogramming
3.4. Programmed Cell Death
3.4.1. Ferroptosis
3.4.2. Pyroptosis
3.4.3. Necroptosis
4. Signaling Pathways During the Renal Tubular Repair Process
4.1. Wnt
4.2. Notch
4.3. Hedgehog
5. Emerging Therapeutic Strategies and Future Directions
5.1. Exosomes in Kidney Injury and Repair
5.2. Metabolic Interventions
5.3. Clearance of Senescent Cells
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AKI | Acute kidney injury |
CKD | Chronic kidney disease |
PTCs | Proximal tubular epithelial cells |
GSDMD | Gasdermin D |
IL-1β | Interleukin-1β |
RIPK | Receptor-interacting protein kinase |
MLKL | Mixed lineage kinase domain-like protein |
TCF/LEF | T-cell factor/lymphoid enhancer factor |
Notch1–4 | Notch receptors |
TCA | Tricarboxylic acid cycle |
Dll | Delta-like |
Jag | Jagged |
Hh | Hedgehog |
Shh | Sonic Hedgehog |
Ihh | Indian Hedgehog |
Dhh | Desert Hedgehog |
Ptch/Smo | The primary transmembrane receptors comprise patched and smoothened |
Havcr1/KIM1 | Kidney Injury Molecule 1 |
Krt8 | Keratin 8 |
Krt20 | Keratin 20 |
Lcn2/NGAL | Neutrophil gelatinase-associated lipocalin |
SOX9+ | SOX9-positive |
CDH6 | Cadherin 6 |
NF-κB | Nuclear factor κB |
CREs | Conserved cisregulatory elements |
P21 | P21CIP1 |
P16 | P16INK4A/pRb |
CDKS | Cyclin-dependent kinases |
CKIs | Cyclin-dependent kinase inhibitors |
ETC | Electron transport chain |
DRP1 | Dynamin-Related Protein 1 |
MFN1 | Mitofusin 1 |
MFN2 | Mitofusin 2 |
OPA1 | Optic Atrophy 1 |
PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator-1α |
FAO | Fatty acid oxidation |
ATP | Adenosine triphosphate |
TFAM | Mitochondrial transcription factor A |
PPARα | Proliferator-activated receptor α (PPARα) |
KLF15 | Krüppel-like factor 15 |
TGFβ | Transforming growth factor-beta |
H2K4Me1 | Histone 3 lysine 4 monomethylation |
OXPHOS | Oxidative phosphorylation |
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Regulator | In Vivo Models | In Vitro Models | Target or Mechanism | Influence on Kidney | Reference |
---|---|---|---|---|---|
Fibroblast growth factor 21 | UUO | TGF-β | Negative feedback mode | Inhibits renal tubulointers | [100] |
Sirtuin 6 | UUO, IR | TGF-β | Deacetylation of histone H3K56 | Inhibits renal tubulointerstitial fibrosis | [101] |
Kallistatin | UUO | TGF-β | Modulation of Wnt4/β-catenin signaling | Inhibition of epithelial–mesenchymal transition | [102] |
Transmembrane protein 16 A | Ang II | Ang II | Inhibited the expression Wnt3a, LRP5, and active β-catenin | Inhibits renal tubulointerstitial fibrosis | [103] |
Pregnane X receptor | UUO | TGF-β | Interacting with p53 and inhibiting the Wnt7a/β-catenin | Alleviates renal fibrosis | [104] |
Combined melatonin and poricoic acid A | IR | HK2: hypoxia–reoxygenation, TGF-β | Disturbed the interaction of Smad3 and β-catenin | Inhibits renal fibrosis | [105] |
Claudin-5 | UUO | Primary podocytes | Downregulation of Wnt inhibitory factor-1 | Promotes kidney fibrosis | [106] |
FoxM1 | UUO, FA | Ang II | Transcriptionally regulating multi-Wnts expressions | Promotes kidney fibrosis | [107] |
Brahma-related gene-1 | UUO | TGF-β, Etoposide | Inhibition of autophagy | Promotes tubular senescence and renal fibrosis | [108] |
IKKα | UUO, IR | TGF-β | Enhanced β-catenin nuclear translocation | Aggravates renal fibrogenesis | [109] |
Indoleamine-2,3-Dioxygenase | IR | No vitro models | Unknown | Inducing kidney fibrosis after AKI | [110] |
miR-21 | Aristolochic acid | Aristolochic acid | Unknown | Promotes AKI-CKD transition | [111] |
lncRNA-H19 | IR | TGF-β | Downregulation of miR-196a | Inducing kidney fibrosis | [112] |
Receptors | Receptors’ Source | Ligands | Target Genes | Models | Mechanism | Influence | References |
---|---|---|---|---|---|---|---|
Notch 1 | Vascular endothelial cells | Dll4 | HEY1, HEY2, NOTCH3 | HUVECs: combinant human DLL4 and recombinant human Jag1 | EMT | Promoting renal fibrosis | [127] |
Notch1 | TECs | Dll1 | Unknown | HK2/mice: cisplatin | Promoting kidney inflammation | Promoting renal injury | [128] |
Notch1 | TECs | Dll4 | Unknown | Mice: IRI PTECs: hypoxia–reoxygenation | Causing prosenescence | Renal maladaptive repair | [129] |
Notch1 | TECs | Jagged-1 | Hes-1 and Hey-1 | Mice, TECs: Gremlin | Activation of NF-κB pathway | Proinflammation | [130] |
Notch1 | Macrophage | Dll4 | Hes1, Hey1, and Hey2 | RAW264.7: Indoxyl Sulfate | Interplay of OATP2B1 | Proinflammation | [131] |
Notch1 | Macrophage | Unknown | IKK-B and p65 | RAW 264.7 /mice: high glucose | M1 polarization | Promoting renal fibrosis | [122] |
Notch2 | TECs | Jagged-1 | Hes-1 | Mice: IRI | STAT3 phosphorylation and upregulation of survivin | Promoting functional and structural recovery | [126] |
Notch2 | TECs | Hes1 | Unknown | Rats: IR | Promoting inflammation and apoptosis | Promoting renal injury | [132] |
Notch3 | TECs and podocyte | Unknown | Unknown | Mice: lipopolysaccharide | TLR4/NOTCH3 | Renal apoptosis and inflammation | [133] |
Regulator | In Vivo Models | In Vitro Models | Regulating Mechanisms | Influence on Renal | Reference |
---|---|---|---|---|---|
BPPs | UUO | TGF-β | Decreased E-cadherin expression | Ameliorating renal fibrosis and EMT | [140] |
Kaempferol | Hypertensive | TGF-β | I nhibiting the activation of Shh and Gli through increasing the expression of Sufu | Inhibiting renal fibrosis and EMT | [138] |
CDGSH iron sulfur domain 2 | LPS | LPS | Unknown | Alleviating septic AKI | [135] |
Hydroxytyrosol | IR | H/R | Inhibiting apoptosis | Inh i biting apoptosis | [136] |
Mechanism | Examples | Advantages | Challenges | Current Stage |
---|---|---|---|---|
Exosomes | FRC exosomes | Suitable for delivery, with a wide range of sources, with a variety of contents Reducing inflammation and fibrosis Promoting tissue repair and regeneration | They lack tissue specificity and targeting, and the mixed effects of their contents are not clear, lacking long-term safety. | Preclinical research |
Metabolic interventions | Small-molecule inhibitors of PFKFB3: 3PO | Improving renal energy metabolism Reducing inflammation and fibrosis | Drug side effects Individual differences Long-term efficacy and safety | More preclinical studies A few clinical trials (SGLT2) |
Clearance of senescent cells | Combination of dasatinib and quercetin | Reducing inflammation and fibrosis Promoting tissue repair and regeneration Improving treatment outcomes and prognosis | Potential adverse reactions Clearance efficiency and specificity issues Adaptability to disease stages | More preclinical studies Less clinical data in age-related diseases |
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Xu, D.; Zhang, X.; Pang, J.; Li, Y.; Peng, Z. Mechanisms of Acute Kidney Injury–Chronic Kidney Disease Transition: Unraveling Maladaptive Repair and Therapeutic Opportunities. Biomolecules 2025, 15, 794. https://doi.org/10.3390/biom15060794
Xu D, Zhang X, Pang J, Li Y, Peng Z. Mechanisms of Acute Kidney Injury–Chronic Kidney Disease Transition: Unraveling Maladaptive Repair and Therapeutic Opportunities. Biomolecules. 2025; 15(6):794. https://doi.org/10.3390/biom15060794
Chicago/Turabian StyleXu, Dongxue, Xiaoyu Zhang, Jingjing Pang, Yiming Li, and Zhiyong Peng. 2025. "Mechanisms of Acute Kidney Injury–Chronic Kidney Disease Transition: Unraveling Maladaptive Repair and Therapeutic Opportunities" Biomolecules 15, no. 6: 794. https://doi.org/10.3390/biom15060794
APA StyleXu, D., Zhang, X., Pang, J., Li, Y., & Peng, Z. (2025). Mechanisms of Acute Kidney Injury–Chronic Kidney Disease Transition: Unraveling Maladaptive Repair and Therapeutic Opportunities. Biomolecules, 15(6), 794. https://doi.org/10.3390/biom15060794