Abstract: TH-PO0209
SerpinA3k Deficiency Protects Against Kidney Fibrosis Through Preservation of the PPARα-Cyp4A14 Axis
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Gómez Trujillo, Dulce Deifilia, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Mexico City, CDMX, Mexico
- Olivares-Schietekat, Sebastián, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Mexico City, CDMX, Mexico
- García Hernández, Lucero, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Mexico City, CDMX, Mexico
- González Soria, Isaac, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Mexico City, CDMX, Mexico
- Villalva, Rosalba Pérez, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Mexico City, CDMX, Mexico
- Marquina Castillo, Brenda N., Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Departamento de Patologia, Mexico City, CDMX, Mexico
- Sanchez Navarro, Andrea, National Institutes of Health, Bethesda, Maryland, United States
- Bobadilla, Norma, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Mexico City, CDMX, Mexico
Background
SerpinA3k (SA3k) is a serine protease inhibitor that, beyond its canonical function, has emerged from our studies as a regulator in renal disease. We previously identified urinary SA3 levels (UrSA3) as an early biomarker of fibrosis and CKD in rats and humans. We also demonstrated that elevated UrSA3 levels reflect active lupus nephritis and correlate with therapeutic response. Mechanistically, we found that SA3k deficiency enhances antioxidant defenses after ischemia/reperfusion injury and protects against metabolic dysfunction in type 2 diabetes, underscoring its broader pathophysiological relevance. The purpose of this study was to investigate the impact of SA3k deficiency on tubulointerstitial fibrosis (TIF) and to elucidate the underlying regulatory mechanisms.
Methods
A total of 16 male wild-type (WT) and 16 male SA3k-deficient (KO) mice were randomly assigned to either a sham surgery (n=6) or a unilateral ureteral obstruction (UUO, n=10). The mice were followed for 7 days. TIF was quantified by morphometric analysis and by assessing fibrotic and epithelial-mesenchymal transition markers. The inflammatory response (InRes) was evaluated through cytokine expression profiling. In addition, transcriptomic analysis was performed using RNA sequencing. The data were analyzed using two-way ANOVA with Tukey’s post hoc test, significance was defined as p<0.05.
Results
In WT mice, UUO reduced GFR and markedly increased TIF. This was associated with elevated renal SA3k expression and an upregulation of the profibrotic markers TGF-β, β-catenin, α-SMA, and vimentin. In contrast, SA3k-deficient mice (KO+UUO) showed preserved renal function and significantly attenuated TIF. The InRes differed between groups: WT+UUO mice exhibited increased OPN, pNFκB, and IL-10, whereas these were not observed in KO+UUO mice. RNA-seq, RT-PCR, and protein analysis revealed lower basal Cd274 expression in KO mice, and an upregulation in WT+UUO mice compared to KO+UUO. Moreover, WT+UUO mice exhibited a significant reduction in PPARα and its target, Cyp4a14. In contrast, KO+UUO mice maintained this axis comparable to the sham group.
Conclusion
Our findings identify SA3k as a driver of TIF, while its deficiency mitigates fibrosis, preserves renal function, and reshapes inflammatory-metabolic signaling by maintaining the PPARα/Cyp4a14 axis. These results highlight SA3k as a promising therapeutic target in CKD.
Funding
- Government Support – Non-U.S.