Abstract: PO2483
Hypervitaminosis A Contributes to Kidney Injury Through Excessive Endoplasmic Reticulum Stress in CKD
Session Information
- CKD: Metabolism, Epigenetics, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Adachi, Yuichiro, Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School., Tokushima, Tokushima, Japan
- Masuda, Masashi, Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School., Tokushima, Tokushima, Japan
- Sasaki, Kohei, Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School., Tokushima, Tokushima, Japan
- Ohminami, Hirokazu, Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School., Tokushima, Tokushima, Japan
- Yamanaka-Okumura, Hisami, Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School., Tokushima, Tokushima, Japan
- Yamamoto, Hironori, Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School., Tokushima, Tokushima, Japan
- Taketani, Yutaka, Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School., Tokushima, Tokushima, Japan
Background
Endoplasmic reticulum (ER) stress is activated upon the accumulation of misfolded proteins in the ER. PERK signal, one of the downstream pathways of ER stress response, mediates some transcription factors such as activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP). It has been known CHOP induces renal dysfunction and leads to chronic kidney disease (CKD) via apoptosis. ATF4 promotes transcriptional activation of DNA damage-inducible protein 34 (GADD34/Ppp1r15a), which is the negative-feedback protein of PERK signaling and essential for cell survival. It is reported that the levels of plasma vitamin A and its metabolites, all-trans retinoic acid (ATRA), increase in CKD patients from the early CKD stage. One recent report shows excessive vitamin A in CKD patients induces renal dysfunction, however, the effects of ATRA on ER stress have been unclear. In this study, we investigated the role of ATRA on ER stress in the kidney of CKD.
Methods
NIH3T3 cells were treated with 100 nM ATRA and 100 nM thapsigargin (Tg), a major ER stress inducer, for 12 to 48 hours. Eight-week-old male C57BL/6J mice were fed a control diet (control) or adenine-contained diet (0.2%) and treated with either vehicle (CKD) or ATRA (10 mg/kg/3 days) for 8 weeks (CKD + ATRA). Gene and protein expressions were evaluated by real-time qPCR and western blotting.
Results
Although ATRA did not change the mRNA and protein expressions of ATF4 and CHOP in NIH3T3 cells, ATRA additively increased ATF4 and CHOP induced by Tg. Interestingly, ATRA decreased GADD34 protein expression induced by Tg, even though ATRA increased Tg-induced expression of ATF4, the positive upstream regulator of GADD34. The evaluation of protein levels of cleaved-Caspase 3, a major apoptosis marker, and flow cytometry indicated ATRA increases Tg-induced apoptosis. ATRA did not change CKD-induced high plasma levels of phosphate and BUN. However, ATRA increased the protein expression of BiP, CHOP, and cleaved-Caspase 3, but decreased GADD34 expression in CKD mice. Furthermore, the evaluations of Masson’s Trichrome staining in the kidney suggested ATRA increase CKD-induced fibrosis.
Conclusion
These results indicate hypervitaminosis A on CKD exacerbates ER stress via decreasing GADD34, which induces kidney injury.