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 positive control.  

In our previous newsletter, we have shown that, in accordance with the literature, Salsalate has slowed PKD progression in our ADPKD mouse model (click here to view the effect of Salsalate on kidney weight and blood urea levels). 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).  

Line figure showing response of ADPKD mice to Salsalate and control treatment

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), Salsalatefed Pkd1 KO mice have significantly lower kidney volume at post-natal day (PND) 97 (P<0.001) 

Graph bar showing response of ADPKD mouse model to Salsalte vs control treatment Histopathology images show example images of kidneys of ADPKD mice showing cystic pathology which improves upon salsalate treatment.

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).  

Survival curve showing how many mice on average survive following Salsalate treatment vs control treatment int he ADPKD mouse model.

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.  

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.  

Bar graph showing example results using rhe nephrotoxicity assay.

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).

Be the first to know – get this news straight to your inbox

InnoSer provides a variety of validated in vitro and in vivo screening tests for nephrology. If you require additional information, feel free to reach out, and we will respond within a few days.

We provide a monthly update from our InnoSer labs containing up to date scientific insights into our research services. To get news straight to your inbox please sign up here.