Zihui Yu1,2, Ziying Xu3, Yuan Liang1, Pengbin Yin4,5, Yue Shi1, Jiayi Yu6, Junfeng Hao7, Ting Wang6, Weimin Ci8,2,9. 1. Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China. 2. University of Chinese Academy of Sciences, Beijing, China. 3. Capital Institute of Pediatrics, Beijing, China. 4. Department of Orthopedics, Chinese PLA General Hospital, Beijing, China. 5. National Clinical Research Center for Orthopedics, Beijing, China. 6. Beijing Research Institute of Chinese Medicine, Beijing, China. 7. Core Facility for Protein Research, Institute of Biophysics, Beijing, China. 8. Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China ciwm@big.ac.cn. 9. Institute for Stem Cell and Regeneration, Beijing, China.
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.
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.
Authors: Tero I Ala-Kokko; Shivaprakash J Mutt; Sara Nisula; Juha Koskenkari; Janne Liisanantti; Pasi Ohtonen; Meri Poukkanen; Jouko J Laurila; Ville Pettilä; Karl-Heinz Herzig Journal: Ann Med Date: 2016-01-22 Impact factor: 4.709
Authors: Bastian Linder; Anya V Grozhik; Anthony O Olarerin-George; Cem Meydan; Christopher E Mason; Samie R Jaffrey Journal: Nat Methods Date: 2015-06-29 Impact factor: 28.547