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Updated: Jul 4, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
VDR regulates mitochondrial function as a protective mechanism against renal tubular cell injury in diabetic rats
Hong Chen1, Hao Zhang1, Ai-Mei Li1
1Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China.
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.
Insights
Vitamin D receptor (VDR) activation restores mitochondrial function in diabetic kidney disease by improving mitophagy and Mfn2-MAMs-Fundc1 pathway. VDR agonists protect against renal tubulointerstitial fibrosis by regulating mitochondrial health.
Area of Science:
- Nephrology
- Endocrinology
- Cell Biology
Background:
- Diabetic kidney disease (DKD) is characterized by renal tubulointerstitial fibrosis and mitochondrial dysfunction.
- The role of Vitamin D receptor (VDR) in regulating mitochondrial function in DKD remains incompletely understood.
Purpose of the Study:
- To elucidate the regulatory effect and mechanism of VDR on mitochondrial function in renal tubular epithelial cells under diabetic conditions.
- To investigate VDR's role in mitigating renal tubulointerstitial fibrosis in diabetic rats.
Main Methods:
- Diabetic rat models (streptozotocin-induced) and human renal tubular cells (HK-2) under high glucose/TGF-β stimulation were utilized.
- Mitochondrial function parameters, including mitophagy, ROS, ATP, and membrane potential, were assessed.
- Interventions included VDR agonists (calcitriol, paricalcitol), autophagy inhibitors, and genetic manipulation of VDR and Mfn2.
Main Results:
- VDR expression was significantly decreased in diabetic kidneys.
- VDR activation by calcitriol attenuated renal fibrosis, reduced albuminuria, and improved mitochondrial function (mitophagy, reduced ROS, enhanced ATP and Complex V activity).
- VDR directly interacts with Mfn2, and this interaction is crucial for restoring mitochondria-associated ER membranes (MAMs) integrity and mitophagy via the Mfn2-MAMs-Fundc1 pathway.
Conclusions:
- Activated VDR restores mitophagy and mitochondrial function in renal tubular cells through the Mfn2-MAMs-Fundc1 pathway.
- VDR agonists ameliorate diabetic renal tubulointerstitial fibrosis, at least partially, by regulating mitochondrial function.
