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Vitamin C Deficiency Causes Cell Type-Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model
Zihui Yu1,2, Ziying Xu3, Yuan Liang1
1Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China.
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.
Insights
Vitamin C deficiency causes kidney injury by altering DNA and RNA epigenetic modifications. Supplementation may help prevent kidney damage, highlighting vitamin C
Area of Science:
- Renal physiology
- Epigenetics
- Nutritional science
Background:
- Vitamin C deficiency is common in kidney disease patients.
- The role of vitamin C in kidney health and disease is not well understood.
- Its function as an epigenetic regulator in the kidneys remains largely unknown.
Purpose of the Study:
- To investigate the role of vitamin C in kidney homeostasis and pathogenesis.
- To explore vitamin C's function as an epigenetic regulator in the kidneys.
Main Methods:
- Utilized a vitamin C-deficient mouse model (Gulo knock-out).
- Employed whole-genome bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and single-cell RNA sequencing.
- Analyzed DNA/RNA epigenetic modifications and proximal tubule cell injury.
Main Results:
- Vitamin C deficiency induced acute tubular necrosis (ATN) in mice.
- Epigenetic modifications in proximal tubule and endothelial cells led to tubule injury and hypoxia.
- Loss of DNA hydroxymethylation and gain of DNA hypermethylation preceded tubule necrosis, establishing causality.
- Vitamin C derivative supplementation prevented cisplatin-induced ATN.
Conclusions:
- Vitamin C is critical for maintaining kidney homeostasis and preventing pathogenesis.
- Vitamin C supplementation may reduce the risk of kidney injury.
