Abstract: TH-PO0247
5-HT2B Antagonism Reduces Renal Cortical Fibrosis and Restores Kidney Function in an Adenine-Induced CKD Rat Model
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
- McAlister, Kai W., The University of Arizona College of Pharmacy, Tucson, Arizona, United States
- Janda, Jaroslav, The University of Arizona College of Pharmacy, Tucson, Arizona, United States
- Schnellmann, Rick G., The University of Arizona College of Pharmacy, Tucson, Arizona, United States
Background
Renal fibrosis is a debilitating hallmark of chronic kidney disease (CKD), which impairs both the structural and functional integrity of the kidney. Mitochondrial dysfunction has previously been shown to play a critical role in facilitating the onset/progression of fibrosis. Conversely, mitochondrial biogenesis (MB), the generation of new and functional mitochondria, may provide an effective strategy for combating renal fibrosis in CKD.
MARY1 is a novel 5-HT2B antagonist that induces mitochondrial biogenesis (MB), restores renal function, and reduces renal fibrosis in a mouse model of acute kidney injury (AKI). We hypothesized that treatment with MARY1 would also improve kidney function and reduce renal fibrosis in an adenine-induced CKD rat model.
Methods
Rats were divided into three groups: 1) rats receiving a control diet (regular chow), 2) rats receiving a 0.2% adenine-supplemented diet with daily vehicle [saline + 0.1% DMSO] injection, and 3) rats receiving 0.2% adenine-supplemented diet with daily MARY1 treatment [0.3 mg/kg] (n=8/group). Rats were exposed to adenine diet and treated for 4 weeks. Following treatment, kidneys were harvested, and cortical tissue was analyzed via immunoblotting and histological staining analysis.
Results
Our results show that 0.2% adenine-supplemented was sufficient to induce CKD in rats as measured by urinary ACR. Moreover, we showed that MARY1 was able to increase PGC1a, the master regulator of mitochondrial biogenesis, by ~2.7-fold. In addition, MARY1 reduced overall tubulointerstitial fibrosis and several markers of fibrosis and epithelial-mesenchymal transition, including collagen-1 by ~28%, PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3) by ~56%, and VCAM1 by ~49% (vascular cell adhesion molecule 1).
Importantly, KIM1 (Kidney Injury Molecule 1), a key marker of tubular injury, was reduced by 52% in rats treated with MARY1. NGAL (neutrophil gel-associated lipocalin), another marker of kidney injury, was also reduced by ~70%. Finally, serum blood urea nitrogen was significantly reduced in rats treated with MARY1.
Conclusion
These results suggest a therapeutic potential of MARY1 and other 5-HT2B antagonists in ameliorating mitochondrial dysfunction and reducing renal fibrosis in CKD. More research is needed to understand the precise mechanism underlying these protective effects.
Acknowledgment
We would like to acknowledge the Tissue Acquisition and Cellular/Molecular Analysis Core for generating tissue slides for histological analysis.
Funding
- NIDDK Support