Preclinical evaluation of tolvaptan and salsalate combination therapy in a Pkd1-mouse model

Xuewen Song; Wouter N Leonhard; Anish A Kanhai; Gregory R Steinberg; York Pei; Dorien J M Peters

doi:10.3389/fmolb.2023.1058825

Preclinical evaluation of tolvaptan and salsalate combination therapy in a Pkd1-mouse model

Front Mol Biosci. 2023 Jan 19:10:1058825. doi: 10.3389/fmolb.2023.1058825. eCollection 2023.

Authors

Xuewen Song¹, Wouter N Leonhard², Anish A Kanhai², Gregory R Steinberg³, York Pei¹, Dorien J M Peters²

Affiliations

¹ Division of Nephrology, University Health Network and University of Toronto, Toronto, ON, Canada.
² Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
³ Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada.

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder and an important cause of end stage renal disease (ESRD). Tolvaptan (a V2R antagonist) is the first disease modifier drug for treatment of ADPKD, but also causes severe polyuria. AMPK activators have been shown to attenuate cystic kidney disease. Methods: In this study, we tested the efficacy of the combined administration of salsalate (a direct AMPK activator) and tolvaptan using clinically relevant doses in an adult-onset conditional Pkd1 knock-out (KO) mouse model. Results: Compared to untreated Pkd1 mutant mice, the therapeutic effects of salsalate were similar to that of tolvaptan. The combined treatment tended to be more effective than individual drugs used alone, and was associated with improved kidney survival (p < 0.0001) and reduced kidney weight to body weight ratio (p < 0.0001), cystic index (p < 0.001) and blood urea levels (p < 0.001) compared to untreated animals, although the difference between combination and single treatments was not statistically significant. Gene expression profiling and protein expression and phosphorylation analyses support the mild beneficial effects of co-treatment, and showed that tolvaptan and salsalate cooperatively attenuated kidney injury, cell proliferation, cell cycle progression, inflammation and fibrosis, and improving mitochondrial health, and cellular antioxidant response. Conclusion: These data suggest that salsalate-tolvaptan combination, if confirmed in clinical testing, might represent a promising therapeutic strategy in the treatment of ADPKD.

Keywords: ADPKD; combination therapy; gene expression profiling; preclinical trial; salsalate; tolvaptan.

Grants and funding

This work was supported in part by grants from the Canadian Institutes of Health Research (CIHR) Strategy for Patient Oriented Research (SPOR) program in Chronic Kidney Disease (CAN-SOLVE CKD SCA-145103), Polycystic Kidney Disease Foundation of Canada (to YP and DP), and Dutch Kidney Foundation (NSN 15OKG01 to WL and 17PhD02 to DP and WL). Some of the equipment used in this study was supported by the 3D (Diet, Digestive Tract and Disease) Centre funded by the Canadian Foundation for Innovation and Ontario Research Fund, project number 19442 and 30961.