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Renoprotective effect of GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease in spontaneously diabetic Torii fatty rats

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Abstract

Background

The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders.

Methods

Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague–Dawley rats (n = 7) were injected only with a vehicle.

Results

The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment.

Conclusions

Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.

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Data availability

The data used to support the findings of this study are included within the article.

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Acknowledgments

We thank Ms. Kimie Katayama (Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine), Ms. Junko Asano (Department of Internal Medicine, St. Marianna University School of Medicine), Ms. Naomi Saito and Ms. Michiyo Ohashi (Department of Anatomy, St. Marianna University School of Medicine), for great technical assistance.

Funding

This study was supported by JSPS KAKENHI Grant Number JP 19K11478.

Author information

Authors and Affiliations

  1. Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan

    Shohei Yamada, Jun Tanabe, Takeshi Sugaya, Keiichi Ohata, Daisuke Ichikawa, Shiika Watanabe, Yugo Shibagaki & Atsuko Kamijo-Ikemori

  2. Department of Physiology, St. Marianna University School of Medicine, Kanagawa, Japan

    Yuji Ogura

  3. Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan

    Yoshio Nagai

  4. Institute for Ultrastructural Morphology, St. Marianna University School of Medicine, Kawasaki, Japan

    Yasunori Natsuki

  5. Department of Anatomy, St. Marianna University School of Medicine, Kanagawa, Japan

    Kazuho Inoue, Seiko Hoshino & Atsuko Kamijo-Ikemori

  6. JCHO Tokyo Takanawa Hospital, Tokyo, Japan

    Kenjiro Kimura

Authors
  1. Shohei Yamada
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  2. Jun Tanabe
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Contributions

SY, JT, YO, TS, KO, and AK-I study design. SY, JT, YO, KK, KO, SW, KI, SH, and AK-I data collection. SY and AK-I data analysis. SY, YO, YN, DI, TS, KO, KK, YS, and AK-I data interpretation. SY and AK-I literature search and figure generation and SY, YO, and AK-I writing of the manuscript. All authors approved the final version of the manuscript for publication.

Corresponding author

Correspondence to Atsuko Kamijo-Ikemori.

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Conflict of interest

TS is the Director and a senior scientist at CMIC Holdings Co., Ltd., and KO is a scientist at CMIC Holdings Co., Ltd., which produced the kits for L-FABP analysis. All other authors declare no conflicts of interest.

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Yamada, S., Tanabe, J., Ogura, Y. et al. Renoprotective effect of GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease in spontaneously diabetic Torii fatty rats. Clin Exp Nephrol 25, 365–375 (2021). https://doi.org/10.1007/s10157-020-02007-2

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  • DOI: https://doi.org/10.1007/s10157-020-02007-2

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