Short salsalate administration affects cell proliferation, metabolism, and inflammation in polycystic kidney disease

Anish A Kanhai; Elena Sánchez-López; Thomas B Kuipers; Jan B van Klinken; Kyra L Dijkstra; Inge van der Veen; Hans J Baelde; Xuewen Song; York Pei; Hailiang Mei; Wouter N Leonhard; Oleg A Mayboroda; Dorien J M Peters

doi:10.1016/j.isci.2023.108278

Short salsalate administration affects cell proliferation, metabolism, and inflammation in polycystic kidney disease

iScience. 2023 Oct 19;26(11):108278. doi: 10.1016/j.isci.2023.108278. eCollection 2023 Nov 17.

Authors

Affiliations

¹ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
² Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
³ Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.
⁴ Laboratory Genetic Metabolic Diseases of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁵ Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
⁷ Division of Nephrology, University Health Network and University of Toronto, Toronto, ON, Canada.

Abstract

Metabolic reprogramming is a driver of autosomal dominant polycystic kidney disease (ADPKD) progression and a potential therapeutic intervention route. We showed before that the AMP-associated protein kinase (AMPK) activator salsalate attenuates cystic disease progression. Here, we aim to study the early, direct effects of short salsalate treatment in adult-onset conditional Pkd1 deletion mice. Cystic mice were treated with salsalate for two weeks, after which NMR metabolomics and RNA sequencing analyses were performed. Pkd1 deletion resulted in clear metabolomic dysregulation. Short salsalate treatment has small, but significant, effects, reverting acetylcarnitine and phosphocholine concentrations back to wildtype levels, and showing associations with altered purine metabolism. RNA sequencing revealed that short salsalate treatment, next to restoring energy metabolism toward wildtype levels, also affects cell proliferation and inflammation, in PKD. We show that salsalate positively affects major dysregulated processes in ADPKD: energy metabolism, cell proliferation, and inflammation, providing more insights into its working mechanisms.

Keywords: Biological sciences; Metabolomics; Omics; Transcriptomics.