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Ticagrelor and Dapagliflozin Have Additive Effects in Ameliorating Diabetic Nephropathy in Mice with Type-2 Diabetes Mellitus

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Abstract

Purpose

Ticagrelor and dapagliflozin can suppress the activation of the NOD-like receptor 3 (NLRP3)-inflammasome and activate AMP-activated protein kinase (AMPK). The anti-inflammatory effects of dapagliflozin has been shown to depend on AMPK activation. Dapagliflozin and ticagrelor have been shown to have additive effects on the progression of diabetic cardiomyopathy in BTBR ob/ob mice with type-2 diabetes. We assessed whether dapagliflozin and ticagrelor have additive effects on the activation of the NLRP3-inflammasome and the progression of diabetic nephropathy in mice with type-2 diabetes.

Methods

Eight-week-old BTBR received either no-drug, dapagliflozin (1.5 mg/kg/d), ticagrelor (100 mg/kg/d), or their combination for 12 weeks. Blood was assessed weekly for glucose and urine for glucose and albumin. After 12 weeks, blood creatinine, cystatin C, inflammasome activation, and insulin were assessed by ELISA. Renal cortex samples were assessed by hematoxylin and eosin and periodic acid-Schiff staining. RT-PCR and immunoblotting were used to evaluate fibrosis and the activation of Akt, AMPK and the inflammasome.

Results

Both ticagrelor and dapagliflozin reduced serum creatinine and cystatin C levels and urinary albumin. Both drugs attenuated the increase in glomerular area and mesangial matrix index. Both drugs decreased collagen-1 and collagen-3 expression and the activation of the NLRP3-inflammasome. Both drugs increased P-AMPK levels, but only dapagliflozin increased P-Akt levels. Overall, the protective effects of dapagliflozin and ticagrelor were additive.

Conclusions

Dapagliflozin and ticagrelor attenuated the progression of diabetic nephropathy in BTBR ob/ob mice with additive effects of the combination. This was associated with AMPK activation and reduced activation of the NLRP3 inflammasome, whereas only dapagliflozin increased Akt activation.

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Data Availability

Original research data will be available upon request.

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Funding

The study was funded by an investigator initiated grant from AstraZeneca and the John S. Dunn Chair in Cardiology Research and Education.

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Authors and Affiliations

  1. The Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Yochai Birnbaum

  2. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, BSB 648, Galveston, TX, 77555, USA

    Huan Chen & Yumei Ye

  3. Department of Acupuncture, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Huan Chen

  4. School of Medicine, University of Texas Medical Branch, Galveston, TX, USA

    Dat Tran

  5. Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden

    Sven Nylander

Authors
  1. Yochai Birnbaum
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  5. Yumei Ye
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Contributions

All authors contributed to the study conception and design. Material preparation, experiments, and data collection were performed by Huan Chen, Dat Tran, and Yumei Ye. Data analysis was performed by Yumei Ye and Yochai Birnbaum. Figures were made by Yochai Birnbaum. The first draft of the manuscript was written by Yochai Birnbaum, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yumei Ye.

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Ethics Approval

The experimental designs and animal care were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH Publication No. 85–23, revised 1996) and approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch.

Conflict of Interest

Huan Chen,none; Dat Tran,none; Sven Nylander is an employee of Astra Zeneca; Yochai Birnbaum, Research Grant by Astra Zeneca; Yumei Ye, Research Grant by Astra Zeneca.

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Birnbaum, Y., Chen, H., Tran, D. et al. Ticagrelor and Dapagliflozin Have Additive Effects in Ameliorating Diabetic Nephropathy in Mice with Type-2 Diabetes Mellitus. Cardiovasc Drugs Ther 36, 829–840 (2022). https://doi.org/10.1007/s10557-021-07222-x

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