VDR regulates mitochondrial function as a protective mechanism against renal tubular cell injury in diabetic rats

Hong Chen; Hao Zhang; Ai-mei Li; Yu-ting Liu; Yan Liu; Wei Zhang; Cheng Yang; Na Song; Ming Zhan; Shikun Yang

Redox Biology (Apr 2024)

VDR regulates mitochondrial function as a protective mechanism against renal tubular cell injury in diabetic rats

Hong Chen,
Hao Zhang,
Ai-mei Li,
Yu-ting Liu,
Yan Liu,
Wei Zhang,
Cheng Yang,
Na Song,
Ming Zhan,
Shikun Yang

Affiliations

Hong Chen: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China
Hao Zhang: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China
Ai-mei Li: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China
Yu-ting Liu: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China
Yan Liu: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China
Wei Zhang: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China
Cheng Yang: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China
Na Song: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China
Ming Zhan: Department of Nephrology, The First Affiliated Hospital of Ningbo University, China
Shikun Yang: Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China; Corresponding author. Department of Nephrology The Third Xiangya Hospital, Central South University No.138, Tongzipo Road, Changsha, Hunan Province, 410013, China.

Journal volume & issue: Vol. 70
p. 103062

Abstract

Read online

Purpose: To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status. Methods: The diabetic rats induced by streptozotocin (STZ) and HK-2 cells under high glocose(HG)/transforming growth factor beta (TGF-β) stimulation were used in this study. Calcitriol was administered for 24 weeks. Renal tubulointerstitial injury and some parameters of mitochondrial function including mitophagy, mitochondrial fission, mitochondrial ROS, mitochondrial membrane potential (MMP), mitochondrial ATP, Complex V activity and mitochondria-associated ER membranes (MAMs) integrity were examined. Additionally, paricalcitol, 3-MA (an autophagy inhibitor), VDR over-expression plasmid, VDR siRNA and Mfn2 siRNA were applied in vitro. Results: The expression of VDR, Pink1, Parkin, Fundc1, LC3II, Atg5, Mfn2, Mfn1 in renal tubular cell of diabetic rats were decreased significantly. Calcitriol treatment reduced the levels of urinary albumin, serum creatinine and attenuated renal tubulointerstitial fibrosis in STZ induced diabetic rats. In addition, VDR agonist relieved mitophagy dysfunction, MAMs integrity, and inhibited mitochondrial fission, mitochondrial ROS. Co-immunoprecipitation analysis demonstrated that VDR interacted directly with Mfn2. Mitochondrial function including mitophagy, mitochondrial membrane potential (MMP), mitochondrial Ca2+, mitochondrial ATP and Complex V activity were decreased dramatically in HK-2 cells under HG/TGF-β ambience. In vitro pretreatment of HK-2 cells with autophagy inhibitor 3-MA, VDR siRNA or Mfn2 siRNA negated the activating effects of paricalcitol on mitochondrial function. Pricalcitol and VDR over-expression plasmid activated Mfn2 and then partially restored the MAMs integrity. Additionally, VDR restored mitophagy was partially associated with MAMs integrity through Fundc1. Conclusion: Activated VDR could contribute to restore mitophagy through Mfn2-MAMs-Fundc1 pathway in renal tubular cell. VDR could recover mitochondrial ATP, complex V activity and MAMs integrity, inhibit mitochondrial fission and mitochondrial ROS. It indicating that VDR agonists ameliorate renal tubulointerstitial fibrosis in diabetic rats partially via regulation of mitochondrial function.

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

About the journal

Abstract

Keywords