Abstract: SA-PO162
KLF4/Galectin3 Signaling Axis Promotes Tubular Cell Death and AKI
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Liu, Lishan, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Liu, Kang, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiang, Juanjuan, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Ren, Jiafa, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background
Acute kidney injury (AKI) is a serious clinical condition characterized by a rapid deterioration in renal function. Among the various components of the kidney, renal tubular cells are particularly vulnerable and often sustain the most significant damage during AKI. In clinical practice, AKI can stem from a diverse array of causes including ischemia, exposure to nephrotoxic agents, or sepsis. This diversity raises the question of whether there exists a common pathophysiological mechanism or pathway in renal tubular cells that underlies the development of AKI. Given the lack of effective therapies for the different etiologies of AKI, uncovering its common underlying molecular mechanisms across different causes could have a significant impact on human health.
Methods
We reanalyzed the single-cell RNA-sequencing atlas from four mouse AKI models to identify Galectin3 as a commonly expressed candidate in injured tubular cells. We then confirmed expression of Galectin3 protein in injured mouse and human tissues by immunofluorescence or western blotting. Furthermore, to determine the molecular mechanisms regulating the galectin3 pathway, we utilized the "Cre-loxp" system, conducted bulk RNA-sequencing assays, and employed pharmacological interventions in a mouse model of AKI. Additionally, we examined the molecular mechanisms in an in vitro culture of the human kidney tubular cell line (HK2).
Results
We observed that Galectin3 is significantly up-regulated in all four AKI mouse models and shows a positive correlation with tissue injury in human kidneys affected by AKI. Our ChIP-PCR and luciferase-reporter experiments confirmed the direct binding of the transcription factor KLF4 to a specific sequence of the galectin3 gene promoter, supporting the predictions of the JASPAR database. Furthermore, mice with tubular-specific deletion of KLF4 displayed reduced kidney injury and inflammation, along with lower levels of galectin3 expression in both cisplatin and ischemia-reperfusion-induced AKI. Targeting the KLF4/Galectin3 axis with Kenpaullone and GB1107 demonstrated protective effects against cisplatin-induced cell death and acute kidney injury, respectively.
Conclusion
Our study highlights the critical role of KLF4/Galectin3 axis in the pathogenesis of AKI. Disrupting KLF4/Galectin3 signaling pathway may offer a promising therapeutic approach for the treatment of AKI.
Funding
- Government Support – Non-U.S.