Abstract: FR-PO0682
Combined Treatment with Tolvaptan and TGFB Receptor Type-1 Inhibitor SB525334 Preserves Renal Function and Prevents Renal Fibrosis Better than Tolvaptan Alone in a Mouse Model of ADPKD
Session Information
- Cystic Kidney Diseases: Basic and Translational Research
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Kriegel, Alison J., Augusta University, Augusta, Georgia, United States
- Patil, Chetan N., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder in which kidneys become large due to tubular cyst expansion. This is accompanied by the development of renal fibrosis. Tolvaptan, a V2 vasopressin receptor antagonist, is currently the only FDA-approved drug for treatment of ADPKD. Tolvaptan reduces cyst size and modestly slows the rate of declining renal function, however it has a limited effect on preventing the development of interstitial fibrosis in some studies. There are no approved therapies to address fibrosis in ADPKD. Transforming growth factor beta-1 (TGFB1) is a known driver of both cyst expansion and fibrosis in ADPKD models. We hypothesized that blockade of TGFB1 signaling via inhibition of the TGFB receptor type-1 (TGFR1, ALK5) with SB525334, in combination with tolvaptan treatment, would reduce renal fibrosis and result in a greater improvement in renal function than tolvaptan treatment alone in a mouse model of ADPKD.
Methods
Homozygous male and female Pkd1(nl) mice on a C57BL/6 background received either SB525334 (5 mg/kg/day) or vehicle by i.p. injection beginning at postnatal day 7. On postnatal day 28, approximately when cysts reach maximal size, a subset of each group began receiving tolvaptan (5 mg/kg/day) in daily injections (9-10 mice/treatment group). Animals underwent 24-hour urine collection in metabolic caging, followed by blood and tissue collection under isoflurane anesthetic. Masson's trichrome-stained kidney tissues were subjected to blinded quantification of cystic index and % tissue fibrosis.
Results
Treatment with tolvaptan, SB525334, and tolvaptan + SB525334 all reduced the weight of 2 kidneys a percentage of body weight, when compared to vehicle-treated controls, despite having no effect on body weight. Combined SB525334 and TGFB1 resulted in significantly better creatinine clearance than vehicle or individual treatments. Histological examination revealed that, not only did combination therapy reduce the cystic index and renal fibrosis, it preserved the amount of renal tissue with a normal tubular morphology.
Conclusion
The combination of SB525334 and tolvaptan treatment was more effective preventing renal fibrosis and preserving renal function than tolvaptan treatment alone in a mouse model of ADPKD.
Funding
- Private Foundation Support