The combination of metformin and 2‐deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease

Lian, Xiaoying; Wu, Xiaoyuan; Li, Zhongxin; Zhang, Yingjie; Song, Kai; Cai, Guangyan; Li, Qinggang; Lin, Shupeng; Chen, Xiangmei; Bai, Xueyuan

doi:10.1111/bph.14558

Cited by 56 publications

(46 citation statements)

References 45 publications

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“…However, the bioavailability of oral metformin is only ~50% [26,27]. More recently, oral metformin treatment was reported to slow PKD progression in a miniature pig model using a dose of 41∙7 mg/kg/day [52]. However, the estimated human equivalent dose used for this study is 2∙77 g/day, which is higher than the usual dose (2 g/day) used clinically (see supplementary data) [53].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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BackgroundMultiple preclinical studies have highlighted AMP-activated protein kinase (AMPK) as a potential therapeutic target for autosomal dominant polycystic kidney disease (ADPKD). Both metformin and canagliflozin indirectly activate AMPK by inhibiting mitochondrial function, while salsalate is a direct AMPK activator. Metformin, canagliflozin and salsalate (a prodrug dimer of salicylate) are approved for clinical use with excellent safety profile. Although metformin treatment had been shown to attenuate experimental cystic kidney disease, there are concerns that therapeutic AMPK activation in human kidney might require a higher oral metformin dose than can be achieved clinically.MethodsIn this study, we tested metformin-based combination therapies for their additive (metformin plus canagliflozin) and synergistic (metformin plus salsalate) effects and each drug individually in an adult-onset conditional Pkd1 knock-out mouse model (n = 20 male/group) using dosages expected to yield clinically relevant drug levels.FindingsCompared to untreated mutant mice, treatment with salsalate or metformin plus salsalate improved kidney survival (i.e. blood urea nitrogen <20 mmol/L at the time of sacrifice) and reduced cystic kidney disease severity. However, the effects of metformin plus salsalate did not differ from salsalate alone; and neither metformin nor canagliflozin was effective. Protein expression and phosphorylation analyses indicated that salsalate treatment was associated with reduction in mTOR (mammalian target of rapamycin) activity and cellular proliferation in Pkd1 mutant mouse kidneys. Global gene expression analyses suggested that these effects were linked to restoration of mitochondrial function and suppression of inflammation and fibrosis.InterpretationSalsalate is a highly promising candidate for drug repurposing and clinical testing in ADPKD.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…The blots were subsequently probed with HRP-conjugated anti-mouse (Cat# A0216) or anti-rabbit IgG (Cat# A0208; Beyotime Biotechnology, Beijing, China) at 1:1000. Immunoreactive bands were visualized by enhanced chemiluminescence, and densitometry was performed using ImageJ software (RRID: SCR_003070, Bio-Rad Laboratories)' [131].…”

Section: Subitem 9b-examplementioning

confidence: 99%

Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0

Sert

Ahluwalia

Alam³

et al. 2020

PLoS Biol

1,466

809

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Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature.

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“…Furthermore, liver cysts were reported to be present in all investigated animals. This model was first used in a study by Lian et al published in 2019 [ 193 ], in which the effect of single and combined treatments with 2Deoxy-D-glucose (2DG, an inhibitor of glycolysis reported to reduce cysts growth in mouse PKD models [ 194 , 195 ]) and metformin (an AMP-activated protein kinase inhibitor) on ADPKD progression was investigated. They found that all drug treatments significantly inhibited cyst growth in the ADPKD mini-pig model, the combined therapy being the most effective.…”

Section: In Vivo Research Modelsmentioning

confidence: 99%

An Overview of In Vivo and In Vitro Models for Autosomal Dominant Polycystic Kidney Disease: A Journey from 3D-Cysts to Mini-Pigs

Koslowski

Latapy

Auvray

et al. 2020

IJMS

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable cause of end stage renal disease and, as of today, only a single moderately effective treatment is available for patients. Even though ADPKD research has made huge progress over the last decades, the precise disease mechanisms remain elusive. However, a wide variety of cellular and animal models have been developed to decipher the pathophysiological mechanisms and related pathways underlying the disease. As none of these models perfectly recapitulates the complexity of the human disease, the aim of this review is to give an overview of the main tools currently available to ADPKD researchers, as well as their main advantages and limitations.

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The combination of metformin and 2‐deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease

Cited by 56 publications

References 45 publications

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

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

Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0

An Overview of In Vivo and In Vitro Models for Autosomal Dominant Polycystic Kidney Disease: A Journey from 3D-Cysts to Mini-Pigs

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