Minichromosome maintenance 4 plays a key role in protecting against acute kidney injury by regulating tubular epithelial cells survival and regeneration

Sep 29, 2026

Minichromosome maintenance 4 (MCM4) is investigated as a protective regulator in acute kidney injury (AKI), where tubular epithelial cell survival and regenerative recovery determine outcomes. Using CRISPR/Cas9 to delete MCM4 in mouse tubular cells and adeno-associated virus 9 to enhance MCM4 expression, the study tests cisplatin and ischemic reperfusion models. MCM4 loss worsens injury and apoptosis while MCM4 overexpression improves regeneration. Mechanistically, MCM4 depletion activates 53BP1/p53/p21 signaling, and MAD2B regulates MCM4 transcription via E2F1.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Minichromosome maintenance 4 and kidney injury

p53/53BP1 in AKI development and repair

Methods

Results

Conclusions

Journal of Advanced Research 79 (2026) 277–292 Contents lists available at ScienceDirect Journal of Advanced Research journal [homepage: www. elsevier. com/locate/jare](homepage: www. elsevier. com/locate/jare) Original Manuscript Minichromosome maintenance 4 plays a key role in protecting against acute kidney injury by regulating tubular epithelial cells survival and regeneration Jing Huang, Feng Liu, Zhi-Feng Xu, Hui-Ling Xiang, Qian Yuan, Chun Zhang ⁎ Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China h i g h l i g h t s • The upregulation of MCM4 during AKI development is an adaptive response. • MCM4 exerts an essential role in AKI by regulating 53BP1/p53/p21 signaling axis. • MAD2B regulates the transcription level of MCM4 by effecting the level of E2F1. • Identiﬁcation of MCM4 as the potential therapeutic target during AKI development. g r a p h i c a l a b s t r a c t a r t i c l e i n f o Article history: Received 6 October 2024 Revised 19 February 2025 Accepted 16 March 2025 Available online 17 March 2025 Keywords: Acute kidney injury Kidney repair Minichromosome maintenance 4 P53-binding protein 1 P53/p21 signaling a b s t r a c t Introduction: Minichromosome maintenance 4 (MCM4), a constituent of the MCM family, playing a pivotal role in DNA replication. Although MCM4 expression has been widely linked to various malignant tumors, its role in kidney diseases is not well-studied. This study primarily investigates the role and underlying mechanism of MCM4 in acute kidney injury (AKI). Objectives: Characterizing a novel target of MCM4 in patients with AKI. Methods: We used CRISPR/Cas9 gene editing to delete MCM4 gene in tubular cells from C57BL/6J mice. Adeno-associated virus 9 harboring MCM4 was administered via intraparenchymal injection into the kidney to enhance MCM4 expression in vivo. These mice were used to established cisplatin-and ischemic reperfusion injury (IRI)-induced AKI mouse models, for detecting the functional role of MCM4 in the pathological process of AKI. Results: MCM4 level was increased in the tubules of cisplatin- and IRI-induced AKI mouse models. Compare to wide-type mice, MCM4 knockout mice demonstrated greater degree of histological damage and a higher ratio of apoptotic tubular cells, as well as kidney dysfunction upon cisplatin-and IRI-induced AKI models. Conversely, MCM4 overexpression ameliorated the severity of kidney injury and promoted regenerative capacity of tubular cells during AKI development. Mechanically, loss of MCM4 induced the expression of p53-binding protein 1, activating the p53/p21 pathway and exacerbating AKI progression. Additional, MAD2B, as an upstream molecule of MCM4, regulates the transcription level of MCM4 by affecting the level of E2F1. ⁎ Corresponding author at: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. E-mail address: [drzhangchun@hust.edu.cn](drzhangchun@hust.edu.cn) (C. Zhang). [https://doi.org/10.1016/j.jare.2025.03.032](https://doi.org/10.1016/j.jare.2025.03.032) 2090-1232/© 2025 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). J. Huang, F. Liu, Z.-F. Xu et al. Journal of Advanced Research 79 (2026) 277–292 Conclusions: These ﬁndings demonstrate that MCM4 upregulation during AKI development is an adaptive response that preserves tubular cell regenerative capacity and limits the severity of renal injury, thus highlighting the potential value of MCM4 as a biomarker or therapeutic target in patients with AKI. © 2025 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND licen

FAQs

What is the main goal of the study on MCM4 in AKI?

To characterize MCM4 as a novel target in patients and to define how it influences tubular epithelial cell survival and regeneration during acute kidney injury.

How were MCM4 expression levels manipulated in the experimental models?

MCM4 was deleted in tubular cells using CRISPR/Cas9 in C57BL/6J mice, and it was enhanced in vivo by administering adeno-associated virus 9 carrying MCM4 via intraparenchymal kidney injection.

What changes occur in AKI when MCM4 is knocked out versus overexpressed?

MCM4 knockout leads to greater histological damage, more apoptotic tubular cells, and worse kidney dysfunction, whereas MCM4 overexpression ameliorates injury severity and promotes regenerative capacity.

What signaling mechanism links MCM4 to AKI progression?

MCM4 loss increases expression of 53BP1 and activates the p53/p21 pathway, which exacerbates AKI progression; additionally, MAD2B regulates MCM4 transcription through E2F1.

Sep 29, 2026

Uploaded by Quinn Holloway