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

被引：28
作者：
Chen, Hong [1 ]
Zhang, Hao [1 ]
Li, Ai-mei [1 ]
Liu, Yu-ting [1 ]
Liu, Yan [1 ]
Zhang, Wei [1 ]
Yang, Cheng [1 ]
Song, Na [1 ]
Zhan, Ming [2 ]
Yang, Shikun [1 ,3 ]
机构：
[1] Cent South Univ, Xiangya Hosp 3, Crit Kidney Dis Res Ctr, Dept Nephrol, Changsha, Peoples R China
[2] Ningbo Univ, Dept Nephrol, Affiliated Hosp 1, Nanjing, Peoples R China
[3] Cent South Univ, Dept Nephrol, Xiangya Hosp 3, 138 Tongzipo Rd, Changsha 410013, Hunan, Peoples R China
来源：
REDOX BIOLOGY | 2024年 / 70卷
基金：
中国国家自然科学基金;
关键词：
VDR; Mitochondrial; MAMs; DN; Renal tubular cell; VITAMIN-D; OXIDATIVE STRESS; INHIBITION; DISRUPTION; MITOPHAGY; DYNAMICS; RECEPTOR; CONTACT; FUNDC1;
D O I：
10.1016/j.redox.2024.103062
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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-beta) 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. Coimmunoprecipitation 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-beta 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.
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页数：17
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