Salsalate ameliorates disease progression in ADPKD mouse model

In this newsletter we present in-house validation data of Salsalate on disease progression in the ADPKD mouse model. One of key therapeutic strategies undertaken to provide new and efficacious treatments for ADPKD is targeting key signaling pathways that drive cystic growth. Two major pathogenic mechanisms driving cystic growth in ADPKD patients are increased cAMP and mTORC1 signaling. The well-known and only approved ADPKD therapeutic, Tolvaptan, slows down cyst growth by acting on the cAMP pathway via its antagonistic effect on the Vasopressin receptor 2 (V2R).  

The cellular energy sensor and regulator AMPK has also received much attention as a putative ADPKD therapeutic strategy via its upstream inhibitory effects on the mTORC1 signaling pathway. Salsalate, a pro-drug dimer of salicylate belonging to the family of NSAIDs, activates AMPK through direct interactions with the drug-binding domain of the AMPK beta-1 isoform. As such, Salsalate arises as a key candidate for drug repurposing in ADPKD.  Here, we show that Salsalate (0.25% in food for 10 weeks) reduces 2KW/BW% (Figure 1) and blood urea levels (Figure 2) in the Pkd1 KO ADPKD mouse model (KO induced at PND18). In line with our results, previous research has shown that Salsalate has slowed PKD progression in ADPKD mouse models by improving mitochondrial function and reducing inflammation (Leonhard et al. 2019; Song et al. 2023; Kanhai et al. 2023). 

To evaluate efficacy of novel compounds, various control compounds can be used when running efficacy studies, depending on which model is used. In the P18 ADPKD mouse model, Tolvaptan is frequently used as control compound for efficacy studies, however for drug developers focusing on targeting upstream or downstream targets of the AMPK signaling pathway, Salsalate may be a suitable alternative as positive control.  

FIGURE 1. Salsalate treatment reduces the total kidney to body weight (2KW/BW) ratio in the ADPKD mouse model. Compared to Pkd1 KO mice administered with vehicle (food pellets), Salsalate-administered Pkd1 KO mice show significantly lower 2KW/BW ratio, indicative of a decrease in kidney weight and thus cyst growth (****P<0.0001; Mann-Whitney U test).  

FIGURE 2. Salsalate treatment reduces the blood urea levels in the ADPKD mouse model. Compared to Pkd1 KO mice administered with vehicle (food pellets), Salsalate-administered Pkd1 KO mice show progressive reduction in blood urea levels (mmol/l), indicative of a stable kidney function (PND74: *P=0.0155; PND98: **P=0.0028; PND102: **P=0.0010; PND109: **P=0.0014, vehicle-treated vs Salsalate treated Pkd1 KO mice; mixed effect analysis). 

Interested in performing efficacy studies using InnoSer’s ADPKD mouse model? Consulting with our nephrology study experts will allow you to carry out tailored studies while collecting the most study-appropriate data. We also advise you on the most optimal model selection and study design set-up, taking into account your budget and study timelines to enable you with the most cost-effective solution without sacrificing any important research insights.  

Histopathology evaluations by our in-house veterinary pathologists can be performed to evaluate the efficacy and mechanism of action of new ADPKD-specific compounds by evaluating:  

• Cystic index  
• Cell proliferation (e.g. Ki-67 and BrdU staining) 
• Immune cell infiltration and inflammation (e.g., CD3, CD20, CD4, CD8 etc.,) 
• Fibrosis (special stains; e.g. Masson’s Trichrome or IHC markers e.g. Collagen type III etc.,) 
• Pathology evaluation of renal lesions (e.g., tubular epithelial dilation, glomerular atrophy, tubular casts, etc,.).

Drug development can be an iterative and long process, whereby InnoSer can be [Contact company name]’s dedicated partner, offering fast turnaround times with back-to-back experiments to help you optimise your lead compounds. Curious to learn more about InnoSer’s capabilities within the drug development space?  View our Discovery and Development CRO Services.