Academic Journal
Προβολή σε EDS

miR-145-5p Targets KLF4 to Regulate the SIRT3/GPX4 Axis, Mediating Ferroptosis and Exacerbating Tubular Epithelial Cell Injury in Diabetic Nephropathy.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: miR-145-5p Targets KLF4 to Regulate the SIRT3/GPX4 Axis, Mediating Ferroptosis and Exacerbating Tubular Epithelial Cell Injury in Diabetic Nephropathy.
Συγγραφείς: Tan H; Xianning Central Hospital (The First Affiliated Hospital of Hubei University of Science and Technology), Xianning, Hubei, China., Lu Z; People's Hospital of Tongcheng County, Xianning, Hubei, China., Xu M; The Second Affiliated Hospital of Hubei University of Science and Technology, Xianning, Hubei, China., Wu G; School of Clinical Medicine, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China.; National Demonstration Center for Experimental (General Practice) Education, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China., Cao Y; Xianning Central Hospital (The First Affiliated Hospital of Hubei University of Science and Technology), Xianning, Hubei, China.
Πηγή: Nephrology (Carlton, Vic.) [Nephrology (Carlton)] 2026 Aug; Vol. 31 (8), pp. e70237.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Blackwell Science Country of Publication: Australia NLM ID: 9615568 Publication Model: Print Cited Medium: Internet ISSN: 1440-1797 (Electronic) Linking ISSN: 13205358 NLM ISO Abbreviation: Nephrology (Carlton) Subsets: MEDLINE
Imprint Name(s): Original Publication: Carlton, Vic., Australia : Blackwell Science
Ιατρικοί όροι (MeSH): Ferroptosis*/drug effects , Ferroptosis*/genetics , MicroRNAs*/metabolism , MicroRNAs*/genetics , Epithelial Cells*/pathology , Epithelial Cells*/enzymology , Kruppel-Like Transcription Factors*/metabolism , Kruppel-Like Transcription Factors*/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase*/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase*/genetics , Diabetic Nephropathies*/pathology , Diabetic Nephropathies*/genetics , Diabetic Nephropathies*/enzymology , Sirtuin 3*/metabolism , Sirtuin 3*/genetics , Kidney Tubules*/pathology , Kidney Tubules*/enzymology, Glucose/toxicity ; Humans ; Kruppel-Like Factor 4 ; Signal Transduction ; Cell Line
Περίληψη: Background: To investigate whether miR-145-5p regulates high-glucose-induced ferroptosis and injury in renal tubular epithelial cells through the KLF4/SIRT3/GPX4 signaling axis. Ferroptosis, a regulated form of iron-dependent cell death, has been increasingly implicated in DKD pathogenesis. The present investigation was designed to explore the functional significance and underlying molecular mechanisms of the miR-145-5p/KLF4/SIRT3/GPX4 signalling cascade in ferroptotic cell death of renal tubular epithelial cells during DKD.
Methods: A high-glucose-stimulated in vitro DKD model was constructed using human renal tubular epithelial cells (HK-2) exposed to 25.0 mmol/L glucose. Gene and protein expression profiles were characterised through RT-qPCR, Western blotting and immunofluorescence staining. Cellular viability, apoptotic rates and ferroptosis-associated biomarkers were quantified using CCK-8 assay, flow cytometric analysis, ELISA and JC-1 mitochondrial probe, respectively. Molecular binding interactions were confirmed through dual luciferase reporter assays and co-immunoprecipitation experiments. Intracellular reduced glutathione (GSH) content and GPX4 enzymatic activity were additionally measured to evaluate the functional status of the antioxidant arm of ferroptosis.
Results: High glucose exposure triggered time-dependent cellular damage and ferroptotic responses in HK-2 cells, characterised by elevated miR-145-5p levels alongside diminished KLF4, SIRT3 and GPX4 expression. Forced expression of miR-145-5p aggravated cellular damage and ferroptotic phenotypes, whilst its functional suppression conferred cytoprotection. Mechanistic analyses demonstrated that miR-145-5p directly engages the 3'-UTR of KLF4 to repress its expression. Restoring KLF4 expression attenuated high-glucose-mediated cellular injury and enhanced SIRT3 and GPX4 levels. Co-immunoprecipitation assays verified a physical protein-protein association between KLF4 and SIRT3. Functionally, HG stimulation reduced intracellular GSH content and GPX4 enzymatic activity. These changes were aggravated by miR-145-5p overexpression but were partially reversed by miR-145-5p inhibition or KLF4 overexpression.
Conclusion: In the context of hyperglycemia, miR-145-5p facilitates ferroptotic cell death in renal tubular epithelial cells through KLF4 suppression, consequently attenuating the SIRT3/GPX4 signalling cascade and worsening DKD-related cellular injury. This regulatory axis may constitute a promising molecular intervention target for DKD treatment.
(© 2026 Asian Pacific Society of Nephrology.)
References: L.‐L. Han, S.‐H. Wang, M.‐Y. Yao, and H. Zhou, “Urinary Exosomal microRNA‐145‐5p and microRNA‐27a‐3p Act as Noninvasive Diagnostic Biomarkers for Diabetic Kidney Disease,” World Journal of Diabetes 15, no. 1 (2024): 92–104, https://doi.org/10.4239/wjd.v15.i1.92.
S. Y. Zahari Sham, S. Azwar, K. Y. Wai, et al., “Elucidation of mRNA Targets of miR‐145‐5p in Diabetic Kidney Disease Using Bioinformatics Analysis,” Malaysian Journal of Medicine and Health Sciences 18 (2022): 36–43, https://doi.org/10.47836/mjmhs.18.s21.7.
J. Chu, K. Wang, L. Lu, et al., “Advances of Iron and Ferroptosis in Diabetic Kidney Disease,” Kidney International Reports 9, no. 7 (2024): 1972–1985, https://doi.org/10.1016/j.ekir.2024.04.012.
Y. Jiao, X. Liu, J. Shi, et al., “Unraveling the Interplay of Ferroptosis and Immune Dysregulation in Diabetic Kidney Disease: A Comprehensive Molecular Analysis,” Diabetology and Metabolic Syndrome 16, no. 1 (2024): 86, https://doi.org/10.1186/s13098‐024‐01316‐w.
F. Mu, P. Luo, Y. Zhu, P. Nie, B. Li, and X. Bai, “Iron Metabolism and Ferroptosis in Diabetic Kidney Disease,” Cell Biochemistry and Function 43, no. 4 (2025): e70067, https://doi.org/10.1002/cbf.70067.
L. Zhang, X. Wang, L. Chang, et al., “Quercetin Improves Diabetic Kidney Disease by Inhibiting Ferroptosis and Regulating the Nrf2 in Streptozotocin‐Induced Diabetic Rats,” Renal Failure 46, no. 1 (2024): 2327495, https://doi.org/10.1080/0886022x.2024.2327495.
Z. Liu, Y. Fu, M. Yan, et al., “microRNAs in Kidney Diseases: Regulation, Therapeutics, and Biomarker Potential,” Pharmacology and Therapeutics 262 (2024): 108709, https://doi.org/10.1016/j.pharmthera.2024.108709.
M. Hu, Y. Deng, Z. Weng, et al., “Expression and Clinical Significance of Platelet‐Derived miR‐145‐5p and miR‐6805‐3p in Diabetic Kidney Disease Patients,” Frontiers in Medicine 12 (2026): 1529759, https://doi.org/10.3389/fmed.2025.1529759.
M. Wang, Y. Ding, Y. Hu, et al., “SIRT3 Improved Peroxisomes‐Mitochondria Interplay and Prevented Cardiac Hypertrophy via Preserving PEX5 Expression,” Redox Biology 62 (2023): 102652, https://doi.org/10.1016/j.redox.2023.102652.
Y.‐h. Wang, D.‐y. Chang, M.‐h. Zhao, and M. Chen, “Glutathione Peroxidase 4 Is a Predictor of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus,” Oxidative Medicine and Cellular Longevity 2022 (2022): 2948248.
S. Li and K. Susztak, “Mitochondrial Dysfunction Has a Central Role in Diabetic Kidney Disease,” Nature Reviews Nephrology 21, no. 2 (2024): 77–78, https://doi.org/10.1038/s41581‐024‐00919‐w.
Y. Wang, M. Jin, C. K. Cheng, and Q. Li, “Tubular Injury in Diabetic Kidney Disease: Molecular Mechanisms and Potential Therapeutic Perspectives,” Frontiers in Endocrinology 14 (2023): 1238927, https://doi.org/10.3389/fendo.2023.1238927.
X. Zhou, C. Xu, J. Dong, and L. Liao, “Role of Renal Tubular Programed Cell Death in Diabetic Kidney Disease,” Diabetes/Metabolism Research and Reviews 39, no. 2 (2022): e3596, https://doi.org/10.1002/dmrr.3596.
X. Chen, B. Niu, Z. Zhang, et al., “Low‐Molecular‐Weight Fucoidan Ameliorates Ferroptosis in Diabetic Kidney Disease Through SLC7A11/GSH/GPX4 Activation,” Fitoterapia 185 (2025): 106779, https://doi.org/10.1016/j.fitote.2025.106779.
Y.‐C. Tsai, J.‐C. Huang, P.‐S. Yu, et al., “Sodium–Glucose Cotransporter 2 Inhibitors Ameliorate Glutathione Cysteine Ligase Modifier‐Mediated Oxidative Stress and Subsequent Ferroptosis in Proximal Tubules of Diabetic Kidney Disease,” Redox Report 30, no. 1 (2025): 2528334, https://doi.org/10.1080/13510002.2025.2528334.
Q. Wu, Y. Zhao, and F. Huang, “Metformin Alleviates Renal Tubular Injury in Diabetic Kidney Disease by Activating Mitophagy and Inhibiting Ferroptosis via HIF‐1α/MIOX Axis,” Journal of Pharmaceutical Analysis 15, no. 10 (2025): 101284, https://doi.org/10.1016/j.jpha.2025.101284.
M. S. Rahman, S. Ghorai, K. Panda, et al., “Dr. Jekyll or Mr. Hyde: The Multifaceted Roles of miR‐145‐5p in Human Health and Disease,” Non‐Coding RNA Research 11 (2025): 22–37, https://doi.org/10.1016/j.ncrna.2024.11.001.
S. Yu, Y. Li, X. Lu, et al., “The Regulatory Role of miRNA and lncRNA on Autophagy in Diabetic Nephropathy,” Cellular Signalling 118 (2024): 111144, https://doi.org/10.1016/j.cellsig.2024.111144.
J. Su, Q. Wei, K. Ma, et al., “P‐MSC‐Derived Extracellular Vesicles Facilitate Diabetic Wound Healing via miR‐145‐5p/ CDKN1A‐Mediated Functional Improvements of High Glucose‐Induced Senescent Fibroblasts,” Burns & Trauma 11 (2023): tkad010, https://doi.org/10.1093/burnst/tkad010.
Y.‐Y. Guo, N.‐N. Liang, X.‐Y. Zhang, et al., “Mitochondrial GPX4 Acetylation Is Involved in Cadmium‐Induced Renal Cell Ferroptosis,” Redox Biology 73 (2024): 103179, https://doi.org/10.1016/j.redox.2024.103179.
S. Yang, X. Wang, Y. Zhang, et al., “SIRT3 Regulates CPT1a Acetylation and Fatty Acid Oxidation in Renal Tubular Epithelial Cells Under Diabetic Condition,” Molecular Biology Reports 52, no. 1 (2025): 603, https://doi.org/10.1007/s11033‐025‐10712‐y.
K.‐K. Su, D.‐C. Yu, X.‐F. Cao, et al., “Bone Marrow Mesenchymal Stem Cell‐Derived Exosomes Alleviate Nuclear Pulposus Cells Degeneration Through the miR‐145a‐5p/USP31/HIF‐1α Signaling Pathway,” Stem Cell Reviews and Reports 20, no. 8 (2024): 2268–2282, https://doi.org/10.1007/s12015‐024‐10781‐9.
Q. Jin, T. Liu, F. Ma, et al., “Roles of Sirt1 and Its Modulators in Diabetic Microangiopathy: A Review,” International Journal of Biological Macromolecules 264 (2024): 130761, https://doi.org/10.1016/j.ijbiomac.2024.130761.
Grant Information: 2025AFC118 Hubei Provincial Natural Science Foundation of China; Hubei Xianning Federation of Social Sciences
Contributed Indexing: Keywords: GPX4; KLF4; SIRT3; diabetic nephropathy; ferroptosis; miR‐145‐5p; renal tubular epithelial cells
Substance Nomenclature: 0 (MicroRNAs)
0 (Kruppel-Like Factor 4)
0 (KLF4 protein, human)
0 (Kruppel-Like Transcription Factors)
EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
EC 3.5.1.- (Sirtuin 3)
EC 3.5.1.- (SIRT3 protein, human)
0 (MIRN145 microRNA, human)
IY9XDZ35W2 (Glucose)
Entry Date(s): Date Created: 20260724 Date Completed: 20260724 Latest Revision: 20260726
Update Code: 20260726
PubMed Central ID: PMC13396974
DOI: 10.1111/nep.70237
PMID: 42494277
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1440-1797
DOI:10.1111/nep.70237