Kidney Week

Abstract: FR-PO0183

Novel 5-Hydroxytryptamine 2B Receptor Antagonist MARY1 Restores Kidney Mitochondrial Function and Decreases Inflammation and Fibrosis in a Mouse Model of Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Cardiovascular-Kidney-Metabolic Health

• 601 Cardiovascular-Kidney-Metabolic Health: Basic

Authors

• Coutino Villarreal, Cesar A., The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Cesar A. Coutino Villarreal

• Janda, Jaroslav, The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Jaroslav Janda, PhD

• Scholpa, Natalie, The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Natalie Scholpa, PhD

• Date, Abhijit, The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Abhijit Date, PhD

• Schnellmann, Rick G., The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Rick G. Schnellmann, PhD

Background

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease (ESRD) worldwide and remains a major healthcare burden with limited treatment options. Mitochondrial dysfunction is a hallmark of DKD and contributes to progressive renal decline, making restoration of mitochondrial homeostasis a promising therapeutic strategy. MARY1, a novel 5-hydroxytryptamine 2B receptor antagonist, induces renal mitochondrial biogenesis and improves recovery in multiple kidney injury models. Here, we investigated the therapeutic potential of MARY1 in a mouse model of DKD.

Methods

Male 6-week-old BTBR.Cg-Lep^ob/WiscJ mice and wildtype controls were randomly divided into groups treated daily with vehicle or MARY1 (0.3 mg/kg; IP) for 8 weeks. Body weight, blood, and urine were collected biweekly. At 14-weeks of age, renal cortices were collected for immunoblot analysis to evaluate markers of mitochondrial function, inflammation, fibrosis, and metabolic reprogramming. ATP content and NAD+/NADH ratio were measured and Masson's trichrome staining was used to assess collagen deposition.

Results

While DKD mice displayed increased body weight at all time points, MARY1 treatment reduced weight gain compared to vehicle. Vehicle-treated DKD mice showed a 3-fold increase in blood glucose, which was reduced ~50% by MARY1, indicating decreased disease progression. Urinary albumin:creatinine ratio, a marker of renal dysfunction, increased 6-fold in vehicle-treated DKD mice and was reduced 30% by MARY1. MARY1 improved mitochondrial function, as evidence by a 2-fold increase in PGC-1α and restored ATP and NAD+. MARY1 suppressed maladaptive metabolic reprogramming, as indicated by decreased markers of glycolysis (PKM2), glutaminolysis (GLS), and gluconeogenesis (FBP1). Inflammatory markers TNFR2, NF-κB, and VCAM1 increased in vehicle-, but not MARY1-treated DKD mice. Finally, MARY1 normalized FSP1, PDGFRβ, and COL1 expression, and reduced collagen deposition, indicating decreased renal fibrosis.

Conclusion

Treatment with MARY1 decreases DKD disease progression, as evidenced by reduced renal and mitochondrial dysfunction, and decreased inflammation, and fibrosis. These findings highlight MARY1 as a promising therapeutic candidate for DKD and support its potential to slow or prevent progression to ESRD.

Funding

• Veterans Affairs Support