Salsalate, but not metformin or canagliflozin, slows kidney cyst growth in an adult-onset mouse model of polycystic kidney disease

Leonhard, Wouter N.; Song, Xuewen; Kanhai, Anish A.; Iliuta, Ioan-Andrei; Božović, Andrea; Steinberg, Gregory R.; Peters, Dorien J.M.; Pei, York

doi:10.1016/j.ebiom.2019.08.041

Cited by 59 publications

(77 citation statements)

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“…Similarly, we found that AMPK activation via Metformin had no effect on cell proliferation. Although Metformin was suggested to have beneficial effects on disease progression 27 , the effect of Metformin on cell proliferation and cyst growth has been brought into question by another recent study 28 . Additionally, differences in concentration or time frame of compound treatment could account for the lack of activity observed.…”

Section: Resultsmentioning

confidence: 99%

A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells

Asawa

Danchik

Zahkarov

et al. 2020

Sci Rep

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Autosomal dominant polycystic kidney disease (ADpKD) is one of the most common inherited monogenic disorders, characterized by a progressive decline in kidney function due in part to the formation of fluid-filled cysts. While there is one FDA-approved therapy, it is associated with potential adverse effects, and all other clinical interventions are largely supportive. Insights into the cellular pathways underlying ADpKD have revealed striking similarities to cancer. Moreover, several drugs originally developed for cancer have shown to ameliorate cyst formation and disease progression in animal models of ADpKD. these observations prompted us to develop a high-throughput screening platform of cancer drugs in a quest to repurpose them for ADPKD. We screened ~8,000 compounds, including compounds with oncological annotations, as well as FDA-approved drugs, and identified 155 that reduced the viability of Pkd1-null mouse kidney cells with minimal effects on wild-type cells. We found that 109 of these compounds also reduced in vitro cyst growth of Pkd1-null cells cultured in a 3D matrix. Moreover, the result of the cyst assay identified therapeutically relevant compounds, including agents that interfere with tubulin dynamics and reduced cyst growth without affecting cell viability. Because it is known that several ADpKD therapies with promising outcomes in animal models failed to be translated to human disease, our platform also incorporated the evaluation of compounds in a panel of primary ADPKD and normal human kidney (NHK) epithelial cells. Although we observed differences in compound response amongst ADPKD and NHK cell preparation, we identified 18 compounds that preferentially affected the viability of most ADPKD cells with minimal effects on NHK cells. Our study identifies attractive candidates for future efficacy studies in advanced pre-clinical models of ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) has a prevalence of 1 in 500-1,000 individuals and is the most common inherited kidney disease, accounting for 6-9% of patients on renal replacement therapy. ADPKD is caused mainly by mutations in PKD1 and to a lesser extent in PKD2, GANAB and DNAJB11 genes. The disease is characterized by a progressive decline in kidney function due to the formation of fluid-filled cysts as well as activation of inflammatory and proliferative pathways, typically leading to end-stage renal disease by the fifth or sixth decade of life 1. Although cyst formation in the kidneys is the hallmark of ADPKD, other epithelial organs including the liver and pancreas are also commonly affected 2,3. With the 2018 FDA approval of Tolvaptan, a vasopressin V 2-receptor antagonist, there is now one therapy available to slow disease progression; however, the drug was only approved for patients at risk of rapid disease progression due to its potential side effects. Nevertheless, most interventions focus on alleviating disease-related symptoms.

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Section: Resultsmentioning

confidence: 99%

A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells

Asawa

Danchik

Zahkarov

et al. 2020

Sci Rep

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“…However, although our PKD mice and PCK rats seem to respond differently to pioglitazone, several other data do suggest an overlap in important PKD related mechanisms. Inflammatory processes, increased proliferation and altered fatty acid metabolism are all shared between PCK rats and our PKD mice 44,47 . At the molecular level, mTOR and cAMP related signalling has been shown to drive cyst growth in many models of PKD and both the PCK rat and our PKD mice are capable to respond to inhibitors of those signalling pathways (i.e.…”

Section: Discussionmentioning

confidence: 87%

“…To investigate the effects of a combination treatment in vivo, we performed a preclinical study with our adult-onset PKD mouse model (iKspCre-Pkd1 del , Fig. 2c) 43,44 . Pkd1 gene deletion was induced at post-natal (PN) days 18 & 19 via administration of tamoxifen via oral gavage.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we aimed to further explore whether renal PPARγ expression could be predictive of pioglitazone efficacy. We analysed PPARγ expression in mouse, rat and human kidneys by consulting various publicly available microarray datasets 44,46,47 . All three species show very low Pparg expression, compared to the housekeeping gene Hprt (Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

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Renal cyst growth is attenuated by a combination treatment of tolvaptan and pioglitazone, while pioglitazone treatment alone is not effective

Kanhai

Bange²,

Verburg

et al. 2020

Sci Rep

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Autosomal Dominant polycystic Kidney Disease (ADpKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferatoractivator receptor gamma (ppARγ) agonist pioglitazone slows disease progression in the pcK rat model for pKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPARγ was expressed at surprisingly low levels in mouse, rat and human kidneys. other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow pKD progression. the ongoing phase ii clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADpKD treatment. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, affecting 1 in 2500 individuals 1. The most prominent disease feature is the progressive formation of fluid-filled cysts, mainly in the kidneys and less frequent in liver and pancreas 2. In the majority of patients, the cause of disease is a mutation in the PKD1 (±85%) or PKD2 (±15%) gene, encoding for either polycystin-1 or polycystin-2 3,4. Although the exact mechanisms are not yet completely understood, both PKD1 and PKD2 mutations have been shown to dysregulate many intracellular signalling pathways including mammalian target of rapamycin (mTOR), 5' adenosine monophosphate-activated protein kinase (AMPK), transforming growth factor-beta (TGF-β) and extracellular signal-related kinase (ERK) 5-12. Also, altered fluid secretion involving the cystic fibrosis transmembrane conductance regulator (CFTR) and metabolic alterations (increased glycolysis and reduced fatty acid oxidation) have been reported to contribute to disease progression 13-16. Over the recent years, various interventions based on correcting dysregulated intracellular signalling have been tested in clinical trials 17-21. So far, only the vasopressin V2 receptor antagonist tolvaptan (Jinarc ®), which lowers intracellular cyclic AMP (cAMP) levels in the collecting duct segment of the kidney, was convincingly shown to slow disease progression in patients and is currently available in multiple countries as a treatment option 22-24. While tolvaptan is effective in delaying the loss of renal function, the drug is accompanied by side effects, including polyuria and liver ...

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“…Serum metformin was measured using liquid chromatographytandem mass spectrometry, as described in ref. 45 .…”

Section: Methodsmentioning

confidence: 99%

Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss

et al. 2019

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Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood 1-3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system 4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15. Metformin is one of the most widely used medications in the world. It is a strong base that exists in its protonated form at physiological pH and therefore does not pass through cellular membranes easily. In rodents, oral administration of metformin (250-300 mg kg-1 body weight) results in clinically relevant plasma concentrations of approximately 10-15 μM; however, concentrations in the

show abstract

Salsalate, but not metformin or canagliflozin, slows kidney cyst growth in an adult-onset mouse model of polycystic kidney disease

Cited by 59 publications

References 58 publications

A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells

A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells

Renal cyst growth is attenuated by a combination treatment of tolvaptan and pioglitazone, while pioglitazone treatment alone is not effective

Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss

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