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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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