Salsalate is a pro-drug dimer of salicylate belonging to the family of NSAIDs, activating 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.  

To evaluate the efficacy of your 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 a control compound for efficacy studies. However, for drug developers focusing on upstream or downstream targets of the AMPK signaling pathway, Salsalate may be a suitable alternative as a reference compound. 

In our previous newsletter, we have shown that, in accordance with the literature, Salsalate has slowed PKD progression in our ADPKD mouse model. In accordance with our previous results, here we show that ADPKD mice fed with Salsalate show a significant decrease in kidney volume (assessed via ultrasound; data shown corrected for body weight) (Figure 1) as well as reduced cystic kidney disease severity (cystic index) compared to vehicle control mice (P=0.0001; Figure 2). Here, we also show that treatment with Salsalate was associated with a significant improvement in survival (P=0.0146) Figure 3).  

FIGURE 1. Salsalate treatment (0.25% in food) reduces kidney volume (corrected for body weight) in the ADPKD mouse model. Compared to Pkd1 KO mice administered with vehicle (food pellets), Salsalate–fed Pkd1 KO mice have significantly lower kidney volume at post-natal day (PND) 97 (P<0.001).  

FIGURE 2. Salsalate treatment (0.25% in food) reduces cystic index (%) in the ADPKD mouse model. (A) Compared to Pkd1 KO mice administered with vehicle (food pellets), Salsalate-administered Pkd1 KO mice show a significant decrease in cystic index (P=0.0001), indicative of improvement of the pathophysiological kidney disease. (B) Representative histological image of kidney obtained from healthy mouse. (C) Representative histological image of kidney obtained from Pkd1 KO vehicle-treated mouse. (D) Representative histological image of kidney obtained from Pkd1 KO Salsalate-treated animal. In comparison to vehicle-treated animals, Salsalate-treated mouse have smaller cysts with lower distribution (arrows).  

FIGURE 3. Salsalate treatment (0.25% in food) improves survival of Pkd1 KO mice (P=0.0146).  

New publication featuring InnoSer’s ADPKD Mouse Model 

A new publication using InnoSer’s ADPKD mouse model shows that computational drug discovery approaches arise as an attractive way to identify and understand potential new treatments for traditionally underserved rare diseases.  

In this paper, researchers from Healx show that the anti-parasitic drug, Mebendazole, is a potent anti-cystic agent, ameliorating the diseased kidney phenotype of ADPKD mice (Brownjohn et al. 2024). This was marked by a decrease in cystic index, reduction in kidney volume, and blood urea levels in ADPKD mice. This research shines light on novel drug discovery approaches, aimed to support the discovery and development of novel therapeutics to treat rare diseases such as ADPKD.  

To learn more about our ADPKD mouse model and how it supports research, visit our ADPKD mouse model page.

New Assay Introduction – Nephrotoxicity Assessment 

Given that nephrotoxicity is currently one of the leading causes of drug failure in the drug development process, early-stage tests to rule out nephrotoxicity are imperative to develop safe, efficacious investigational compounds with low toxicity profile.  

InnoSer’s nephrology team is happy to announce that we are now offering comprehensive in vitro services to evaluate and detect potential nephrotoxicity of novel investigational compounds to help de-risk drug development. Compared to current screening models, InnoSer’s conditionally immortalized proximal tubule epithelial cells (ciPTEC) provide superior translational value in closely mimicking human kidney physiology.  

Advantage of performing nephrotoxicity assays using the  ciPTECs lies in accurate identification of nephrotoxic compounds at a very early stage of the drug development.  Therefore, you can move on to the in vivo preclinical stages of your research with significantly less potentially nephrotoxic compounds, resulting in increased confidence of the efficacy and safety profile of your novel compound.  

Briefly ciPTECs can be used to assess drug uptake via influx transporters (OAT1, OAT3), drug-drug interactions, nephrotoxicity (cell viability), drug-transporter interactions, with example application shown in Figure 4. ciPTECs have been shown to have 100% specificity (no false positives) and 75% sensitivity.  

FIGURE 2. Example application of nephrotoxicity assay using ciPTEC. (A) In this study, ciPTECs were used to investigate the mechanistic interactions between methotrexate and cetuximab and how it affects renal methotrexate transport and cytotoxic potential. (B) Results show that cetuximab changes drug transporter function through EGFR signaling in ciPTECs. These changes in transport function increase the nephrotoxic effects of methotrexate and cisplatin. Figures repurposed with permission from Caetano-Pinto et al. (2017).