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Basic Research
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Vitamin C Deficiency Causes Cell Type–Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model

Zihui Yu, Ziying Xu, Yuan Liang, Pengbin Yin, Yue Shi, Jiayi Yu, Junfeng Hao, Ting Wang and Weimin Ci
JASN March 2022, 33 (3) 531-546; DOI: https://doi.org/10.1681/ASN.2021070881
Zihui Yu
1Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
2University of Chinese Academy of Sciences, Beijing, China
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Ziying Xu
3Capital Institute of Pediatrics, Beijing, China
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Yuan Liang
1Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
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Pengbin Yin
4Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
5National Clinical Research Center for Orthopedics, Beijing, China
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Yue Shi
1Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
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Jiayi Yu
6Beijing Research Institute of Chinese Medicine, Beijing, China
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Junfeng Hao
7Core Facility for Protein Research, Institute of Biophysics, Beijing, China
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Ting Wang
6Beijing Research Institute of Chinese Medicine, Beijing, China
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Weimin Ci
1Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
2University of Chinese Academy of Sciences, Beijing, China
8Institute for Stem Cell and Regeneration, Beijing, China
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Significance Statement

Vitamin C levels decline in patients with various kidney diseases, but the role of the vitamin as an epigenetic regulator in the initiation and progression of kidney diseases has not been characterized. Using Gulo−/− mice, which, like humans, entirely depend on dietary vitamin C, we applied single-cell RNA sequencing, whole genome bisulfite sequencing, and methylated RNA immunoprecipitation sequencing to create the first comprehensive renal cell type–specific transcriptional and DNA/RNA methylation profiles. Vitamin C deficiency induced acute tubular necrosis (ATN) and remodeled DNA/RNA epigenetic modifications in a cell type–specific manner. Cisplatin-induced ATN and AKI had similar transcriptional profiles as Gulo−/− mice. An oxidation-resistant vitamin C derivative, APM, can prevent kidney injuries in cisplatin-induced ATN mice. These findings will aid development of vitamin C as an epigenetic therapy for kidney diseases.

Abstract

Background Vitamin C deficiency is found in patients with variable kidney diseases. However, the role of vitamin C as an epigenetic regulator in renal homeostasis and pathogenesis remains largely unknown.

Methods We showed that vitamin C deficiency leads to acute tubular necrosis (ATN) using a vitamin C–deficient mouse model (Gulo knock-out). DNA/RNA epigenetic modifications and injured S3 proximal tubule cells were identified in the vitamin C–deficient kidneys using whole-genome bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and single-cell RNA sequencing.

Results Integrated evidence suggested that epigenetic modifications affected the proximal tubule cells and fenestrated endothelial cells, leading to tubule injury and hypoxia through transcriptional regulation. Strikingly, loss of DNA hydroxymethylation and DNA hypermethylation in vitamin C–deficient kidneys preceded the histologic sign of tubule necrosis, indicating the causality of vitamin C–induced epigenetic modification in ATN. Consistently, prophylactic supplementation of an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, promoted DNA demethylation and prevented the progression of cisplatin-induced ATN.

Conclusions Vitamin C played a critical role in renal homeostasis and pathogenesis in a mouse model, suggesting vitamin supplementation may be an approach to lower the risk of kidney injury.

  • vitamin C
  • DNA methylation
  • N6-methyladenosine
  • acute tubular necrosis
  • renal homeostasis
  • single-cell RNA sequencing
  • ascorbic acid deficiency
  • epigenomics
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (3)
Journal of the American Society of Nephrology
Vol. 33, Issue 3
March 2022
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Vitamin C Deficiency Causes Cell Type–Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model
Zihui Yu, Ziying Xu, Yuan Liang, Pengbin Yin, Yue Shi, Jiayi Yu, Junfeng Hao, Ting Wang, Weimin Ci
JASN Mar 2022, 33 (3) 531-546; DOI: 10.1681/ASN.2021070881

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Vitamin C Deficiency Causes Cell Type–Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model
Zihui Yu, Ziying Xu, Yuan Liang, Pengbin Yin, Yue Shi, Jiayi Yu, Junfeng Hao, Ting Wang, Weimin Ci
JASN Mar 2022, 33 (3) 531-546; DOI: 10.1681/ASN.2021070881
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More in this TOC Section

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  • Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms
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Keywords

  • vitamin C
  • DNA methylation
  • N6-methyladenosine
  • acute tubular necrosis
  • renal homeostasis
  • single-cell RNA sequencing
  • ascorbic acid deficiency
  • epigenomics

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