Therapeutic role of miR-26a on cardiorenal injury in a mice model of angiotensin-II induced chronic kidney disease through inhibition of LIMS1/ILK pathway.
10.1097/CM9.0000000000002978
- Author:
Weijie NI
1
;
Yajie ZHAO
2
;
Jinxin SHEN
3
;
Qing YIN
1
;
Yao WANG
4
;
Zuolin LI
1
;
Taotao TANG
1
;
Yi WEN
1
;
Yilin ZHANG
1
;
Wei JIANG
1
;
Liangyunzi JIANG
1
;
Jinxuan WEI
1
;
Weihua GAN
2
;
Aiqing ZHANG
2
;
Xiaoyu ZHOU
3
;
Bin WANG
1
;
Bi-Cheng LIU
1
Author Information
1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China.
2. Department of Pediatric Nephrology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China.
3. Department of Neonates, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, China.
4. Department of Nephrology, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu 225100, China.
- Publication Type:Journal Article
- MeSH:
Animals;
MicroRNAs/metabolism*;
Angiotensin II/toxicity*;
Mice;
Renal Insufficiency, Chronic/chemically induced*;
Mice, Knockout;
Disease Models, Animal;
Male;
Signal Transduction/genetics*;
LIM Domain Proteins/genetics*;
Mice, Inbred C57BL;
Cell Line;
Humans
- From:
Chinese Medical Journal
2025;138(2):193-204
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD.
METHODS:We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data.
RESULTS:Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes.
CONCLUSIONS:Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
