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Pioglitazone ameliorates ischemia/reperfusion-induced acute kidney injury via oxidative stress attenuation and NLRP3 inflammasome

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Abstract

Acute kidney injury (AKI) induced by renal ischemia/reperfusion injury (IRI) is a severe clinical condition. ROS accumulation, antioxidant pathways deficiency, and inflammation are involved in IRI. Pioglitazone (Pio) exerts anti-inflammatory and antioxidant effects. The aim of this study was to explore the protective effects of pioglitazone against IRI-induced AKI. Pathogen-free Sprague–Dawley (SD) rats were arbitrarily divided into four groups: Sham operation group Control (CON) group, CON + Pio group, I/R + Saline group, and I/R + Pio group. In addition, HK-2 cells were subjected to hypoxia and reoxygenation to develop an H/R model for investigation of the protective mechanism of Pio. Pretreatment with pioglitazone in the model rats reduced urea nitrogen and creatinine levels, histopathological scores, and cytotoxicity after IRI. Pioglitazone treatment significantly attenuated renal cell apoptosis, decreased cytotoxicity, increased Bcl-2 expression, and downregulated Bax expression. Besides, the levels of ROS and inflammatory factors, including NLRP3, ASC, pro-IL-1β, pro-caspase-1, cleaved-caspase-1, TNF-α, IL-6, and IL-1β, in I/R rats and H/R cells were normalized by the pioglitazone treatment. Pioglitazone improved IRI-induced AKI by attenuating oxidative stress and NLRP3 inflammasome activation. Therefore, pioglitazone has the potential to serve as a novel agent for renal IRI treatment and prevention.

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Data availability

The data and material that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

AKI:

Acute kidney injury

I/R:

Ischemia/reperfusion

NLRP3:

Nod-like receptor protein 3

IRI:

Ischemia/reperfusion injury

ROS:

Reactive oxygen species

Pio:

Pioglitazone

SD:

Sprague–Dawley

CON:

Sham operation

H/R:

Hypoxia/reoxygenation

PPAR-γ:

Peroxisome proliferator-activated receptor-γ

GST:

Glutathione transferase

GSH:

Glutathione

GSSG:

Oxidized glutathione

SOD:

Superoxide dismutase

HK-2:

Human kidney 2

PBS:

Phosphate-buffered saline

CCK-8:

Cell Counting Kit-8

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Acknowledgements

The graphical abstracts were created with BioRender software (BioRender.com).

Funding

This work was supported by the Natural Science Foundation of China (No. 82160371 to J.Z., No.82100869 and No.82360162 to P.Y.); Natural Science Foundation in Jiangxi Province grant (No.20212BAB216047 to P.Y., No.20224ACB216009 and No. 20212BAB216051 to J.Z.); the Jiangxi Province Thousands of Plans (No. jxsq2023201105 to P.Y.); Young Elite Scientists Sponsorship Program by JXAST (No. 2023QT05 to J.Z.); and the Hengrui Diabetes Metabolism Research Fund (No. Z-2017-26-2202-4 to P.Y.).

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Authors and Affiliations

  1. Department of Urology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1st Minde Road, Jiangxi, 330006, Nanchang, China

    Zhenfeng Ye, Gaomin Huang, Honglin Hu & Xiaoqing Xi

  2. Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, Nanchang, China

    Jing Zhang

  3. The Second Clinical Medical College, Jiangxi Medical College, Nanchang University, Jiangxi, Nanchang, China

    Zhou Xu & Zhangwang Li

  4. School of Ophthalmology and Optometry, Jiangxi Medical College, Nanchang University, Jiangxi, Nanchang, China

    Bin Tong

  5. Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, Nanchang, China

    Panpan Xia, Yunfeng Shen & Peng Yu

  6. Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Jiangxi, 330006, Nanchang, China

    Panpan Xia & Peng Yu

Authors
  1. Zhenfeng Ye
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Contributions

Zhenfeng Ye and Jing Zhang: reviewing, methodology, funding acquisition. Zhou Xu and Zhangwang Li: writing—original draft preparation. Gaomin Huang and Bin Tong: visualization and investigation. Panpan Xia and Yunfeng Shen: supervision. Honglin Hu and Jianyong Ma: software and validation. Peng Yu and Xiaoqing Xi: conceptualization and funding.

Corresponding authors

Correspondence to Peng Yu or Xiaoqing Xi.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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All animal experiments were approved by the Ethical Committee on Animal Experiments in the Second Affiliate Hospital of Nanchang University (NO.: Review [2019] No. (033); ethical number: NCULAE-20221121086), in compliance with Chinese national or institutional guidelines for the care and use of animals.

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Ye, Z., Zhang, J., Xu, Z. et al. Pioglitazone ameliorates ischemia/reperfusion-induced acute kidney injury via oxidative stress attenuation and NLRP3 inflammasome. Human Cell (2024). https://doi.org/10.1007/s13577-024-01059-w

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