Abstract: TH-PO1114
Kidney Phenotype of Fosl2 Knockout Mice
Session Information
- CKD: Mechanisms - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Ribagorda Bermejo, Marta, Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz, Madrid, Spain
- Pintor Chocano, Aranzazu, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Madrid, Spain
- Sanchez-Nino, Maria Dolores, Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz, Madrid, Spain
- Ortiz, Alberto, Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz, Madrid, Spain
Group or Team Name
- Group of Nephrology, Vascular Pathology, and Hypertension.
Background
Fosl2 is a member of the AP-1 transcription factor family that plays a role in processes such as fibrosis and inflammation. Fosl2 overexpression induced fibrosis and inflammation in multiple organs, being used as a spontaneous model of systemic sclerosis. Fosl2 deficiency decreased the severity of fibrotic and inflammatory processes. However, the role of Fosl2 in kidney disease is unknown.
Methods
In kidney transcriptomics analyses, we found Fosl2 to be upregulated in a murine cisplatin and folic acid-induced acute kidney injury models. To characterize the role of Fosl2 in kidney injury, we generated renal proximal tubule-specific Fosl2 knock-out mice (Fosl2Δtub). The kidney phenotype of Fosl2Δtub mice was characterized by real-time qPCR, immunohistochemistry and Western blotting and primary cell culture.
Results
Contrary to expectations, deletion of Fosl2 in proximal tubular cells led to a pathological kidney phenotype in 3-month-old mice. While serum creatinine and urea levels were similar to WT mice, Fosl2Δtub mice displayed an increased kidney expression of Ngal, an early marker of kidney injury and of pro-inflammatory cytokines in association with higher immune cell infiltration. Moreover, there was evidence of an early fibrotic phenotype (fibronectin 1 and cpt1a mRNA and Sirius Red staining) and of decreased nephroprotective factor (e.g., klotho) expression. In concordance with these results, in primary renal tubular cell culture, there was an increase in pro-inflammatory cytokines and fibrotic markers and a decrease in nephroprotective factors.
Conclusion
Fosl2 deficiency in mouse proximal tubular kidney cells causes subclinical kidney injury. These results highlight the versatility of Fosl2 roles in different tissues and cell types and open a new range of investigation lines for the treatment of kidney disease.
Funding
- Government Support – Non-U.S.