VDR Activation Attenuates Renal Tubular Epithelial Cell Ferroptosis by Regulating Nrf2/HO-1 Signaling Pathway in Diabetic Nephropathy

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2023 Dec 25

PMID 38145959

Authors

Hui Wang

Xiaoyue Yu

Dongwei Liu

Yingjin Qiao

Jinling Huo

Shaokang Pan

Lijuan Zhou

Rui Wang

Qi Feng

Zhangsuo Liu

Affiliations

Soon will be listed here.

Abstract

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN. Renal tubular injury triggered by ferroptosis might be essential in this process. Numerous studies demonstrate that the vitamin D receptor (VDR) exerts beneficial effects by suppressing ferroptosis. However, the underlying mechanism has not been fully elucidated. Thus, they verified the nephroprotective effect of VDR activation and explored the mechanism by which VDR activation suppressed ferroptosis in db/db mice and high glucose-cultured proximal tubular epithelial cells (PTECs). Paricalcitol (PAR) is a VDR agonist that can mitigate kidney injury and prevent renal dysfunction. PAR treatment could inhibit ferroptosis of PTECs through decreasing iron content, increasing glutathione (GSH) levels, reducing malondialdehyde (MDA) generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 (TFR-1), and enhancing the expression of negative ferroptosis mediators including ferritin heavy chain (FTH-1), glutathione peroxidase 4 (GPX4), and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11). Mechanistically, VDR activation upregulated the NFE2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway to suppress ferroptosis in PTECs. These findings suggested that VDR activation inhibited ferroptosis of PTECs in DN via modulating the Nrf2/HO-1 signaling pathway.

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References

Wang B, Qian J, Tang T, Lin L, Yu N, Guo H . VDR/Atg3 Axis Regulates Slit Diaphragm to Tight Junction Transition via p62-Mediated Autophagy Pathway in Diabetic Nephropathy. Diabetes. 2021; 70(11):2639-2651. DOI: 10.2337/db21-0205. View

Hu Y, Liu S, Liu W, Zhang Z, Liu Y, Sun D . Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches. PLoS One. 2021; 16(11):e0259436. PMC: 8568295. DOI: 10.1371/journal.pone.0259436. View

Li L, Li W, Zheng X, Liu Q, Du Q, Lai Y . Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation. Mol Med. 2022; 28(1):11. PMC: 8800262. DOI: 10.1186/s10020-022-00442-3. View

Clark J, Gebhart G, Gonder J, Keeling M, Kohn D . Special Report: The 1996 Guide for the Care and Use of Laboratory Animals. ILAR J. 1997; 38(1):41-48. DOI: 10.1093/ilar.38.1.41. View

Ricciardi C, Gnudi L . Kidney disease in diabetes: From mechanisms to clinical presentation and treatment strategies. Metabolism. 2021; 124:154890. DOI: 10.1016/j.metabol.2021.154890. View

Latunde-Dada G . Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. Biochim Biophys Acta Gen Subj. 2017; 1861(8):1893-1900. DOI: 10.1016/j.bbagen.2017.05.019. View

Stockwell B, Friedmann Angeli J, Bayir H, Bush A, Conrad M, Dixon S . Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017; 171(2):273-285. PMC: 5685180. DOI: 10.1016/j.cell.2017.09.021. View

Coughlan M, Nguyen T, Penfold S, Higgins G, Thallas-Bonke V, Tan S . Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes. Clin Sci (Lond). 2016; 130(9):711-20. DOI: 10.1042/CS20150838. View

Li A, Yi B, Han H, Yang S, Hu Z, Zheng L . Vitamin D-VDR (vitamin D receptor) regulates defective autophagy in renal tubular epithelial cell in streptozotocin-induced diabetic mice via the AMPK pathway. Autophagy. 2021; 18(4):877-890. PMC: 9037529. DOI: 10.1080/15548627.2021.1962681. View

10.

Nakajo T, Katayoshi T, Kitajima N, Tsuji-Naito K . 1,25-Dihydroxyvitamin D attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes. Redox Biol. 2021; 48:102203. PMC: 8646996. DOI: 10.1016/j.redox.2021.102203. View

11.

Tian Y, Lv G, Yang Y, Zhang Y, Yu R, Zhu J . Effects of vitamin D on renal fibrosis in diabetic nephropathy model rats. Int J Clin Exp Pathol. 2014; 7(6):3028-37. PMC: 4097221. View

12.

Dominguez J, Liu Y, Kelly K . Renal iron overload in rats with diabetic nephropathy. Physiol Rep. 2015; 3(12). PMC: 4760458. DOI: 10.14814/phy2.12654. View

13.

Kim S, Kang S, Joo J, Han S, Shin H, Nam B . Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death Dis. 2021; 12(2):160. PMC: 7870666. DOI: 10.1038/s41419-021-03452-x. View

14.

Miotto G, Rossetto M, Di Paolo M, Orian L, Venerando R, Roveri A . Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol. 2019; 28:101328. PMC: 6812032. DOI: 10.1016/j.redox.2019.101328. View

15.

Jha J, Banal C, Chow B, Cooper M, Jandeleit-Dahm K . Diabetes and Kidney Disease: Role of Oxidative Stress. Antioxid Redox Signal. 2016; 25(12):657-684. PMC: 5069735. DOI: 10.1089/ars.2016.6664. View

16.

Chokhandre M, Mahmoud M, Hakami T, Jafer M, Inamdar A . Vitamin D & its analogues in type 2 diabetic nephropathy: a systematic review. J Diabetes Metab Disord. 2015; 14:58. PMC: 4502529. DOI: 10.1186/s40200-015-0186-6. View

17.

Doll S, Porto Freitas F, Shah R, Aldrovandi M, Costa Da Silva M, Ingold I . FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019; 575(7784):693-698. DOI: 10.1038/s41586-019-1707-0. View

18.

Wang Y, Bi R, Quan F, Cao Q, Lin Y, Yue C . Ferroptosis involves in renal tubular cell death in diabetic nephropathy. Eur J Pharmacol. 2020; 888:173574. DOI: 10.1016/j.ejphar.2020.173574. View

19.

Feng Q, Yang Y, Qiao Y, Zheng Y, Yu X, Liu F . Quercetin Ameliorates Diabetic Kidney Injury by Inhibiting Ferroptosis via Activating Nrf2/HO-1 Signaling Pathway. Am J Chin Med. 2023; 51(4):997-1018. DOI: 10.1142/S0192415X23500465. View

20.

Tomita I, Kume S, Sugahara S, Osawa N, Yamahara K, Yasuda-Yamahara M . SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition. Cell Metab. 2020; 32(3):404-419.e6. DOI: 10.1016/j.cmet.2020.06.020. View