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

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

  • Adv Sci (Weinh). 2023 Dec 25:e2305563. doi: 10.1002/advs.202305563.
Hui Wang 1 2 3 4,  Xiaoyue Yu 1 2 3 4,  Dongwei Liu 1 2 3 4,  Yingjin Qiao 5,  Jinling Huo 1 2 3 4,  Shaokang Pan 1 2 3 4,  Lijuan Zhou 6,  Rui Wang 1 2 3 4,  Qi Feng 1 2 3 4,  Zhangsuo Liu 1 2 3 4
Affiliations

Affiliations

  • 1 Research Institute of Nephrology, Zhengzhou University, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.
  • 2 Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.
  • 3 Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China.
  • 4 Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China.
  • 5 Blood Purification Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.
  • 6 Electron Microscopy Laboratory of Renal Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.
PMID: 38145959 DOI: 10.1002/advs.202305563
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.

Keywords

Nrf2/HO-1 signaling pathway; diabetic nephropathy (DN); ferroptosis; renal tubular epithelial cell; vitamin D receptor (VDR).

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