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Vitamin D inhibits ferroptosis and mitigates the kidney injury of prediabetic mice by activating the Klotho/p53 signaling pathway

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Abstract

Diabetic nephropathy (DN) is a serious public health problem worldwide, and ferroptosis is deeply involved in the pathogenesis of DN. Prediabetes is a critical period in the prevention and control of diabetes and its complications, in which kidney injury occurs. This study aimed to explore whether ferroptosis would induce kidney injury in prediabetic mice, and whether vitamin D (VD) supplementation is capable of preventing kidney injury by inhibiting ferroptosis, while discussing the potential mechanisms. High-fat diet (HFD) fed KKAy mice and high glucose (HG) treated HK-2 cells were used as experimental subjects in the current study. Our results revealed that serious injury and ferroptosis take place in the kidney tissue of prediabetic mice; furthermore, VD intervention significantly improved the kidney structure and function in prediabetic mice and inhibited ferroptosis, showing ameliorated iron deposition, enhanced antioxidant capability, reduced reactive oxygen species (ROS) and lipid peroxidation accumulation. Meanwhile, VD up-regulated Klotho, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, and down-regulated p53, transferrin receptor 1 (TFR1) and Acyl-Coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Moreover, we demonstrated that HG-induced ferroptosis is antagonized by treatment of VD and knockdown of Klotho attenuates the protective effect of VD on ferroptosis in vitro. In conclusion, ferroptosis occurs in the kidney of prediabetic mice and VD owns a protective effect on prediabetic kidney injury, possibly by via the Klotho/p53 pathway, thus inhibiting hyperglycemia-induced ferroptosis.

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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

DN:

Diabetic nephropathy

HFD:

High-fat diet

ROS:

Reactive oxygen species

SLC7A11:

Solute carrier family 7 member 11

GPX4:

Glutathione peroxidase 4

TFR1:

Transferrin receptor 1

ACSL4:

Acyl-Coenzyme A synthetase long-chain family member 4

VDR:

Vitamin D receptor

OGTT:

Oral glucose tolerance test

MDA:

Malondialdehyde

GSH:

Glutathione

α-SMA:

Alpha-smooth muscle actin

TGF-β1:

Transforming growth factor-beta 1

VDRE:

Vitamin D receptor element

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82173515, 82003454 & 82373568) and China Postdoctoral Science Foundation (2023M733206). All the funders had no role in the design, analysis, or writing of this article.

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Authors

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HC and XL designed the study; HC performed the study; HC collected and analyzed the data; YJZ, YFM, HLS and LLT helped to collect data and perform experiments; HC drafted the manuscript; XL, YJZ, JXM, WYL and WJL revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jinxin Miao or Xing Li.

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All animal studies were approved by the Life Science Ethics Review Committee of Zhengzhou University (ZZUIRB2021-GZR0141).

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Chen, H., Zhang, Y., Miao, Y. et al. Vitamin D inhibits ferroptosis and mitigates the kidney injury of prediabetic mice by activating the Klotho/p53 signaling pathway. Apoptosis (2024). https://doi.org/10.1007/s10495-024-01955-4

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