Abstract
The development of diabetic nephropathy (DN) could be promoted by the occurrence of tubulointerstitial fibrosis (TIF), which had a closely relationship with mitochondrial dysfunction of renal tubular epithelial cells (RTECs). As a key regulator of metabolic homeostasis, Yin Yang 1 (YY1) played an important role not only in regulating fibrosis process, but also in maintaining mitochondrial function of pancreatic β cells. However, it was not clear whether YY1 participated in maintaining mitochondrial function of RTECs in early DN-associated TIF. In this study, we dynamically detected mitochondrial functions and protein expression of YY1 in db/db mice and high glucose (HG)-cultured HK-2 cells. Our results showed that comparing with the occurrence of TIF, the emergence of mitochondrial dysfunction of RTECs was an earlier even, besides the up-regulated and nuclear translocated YY1. Correlation analysis showed YY1 expressions were negatively associated with PGC-1α in vitro and in vivo. Further mechanism research demonstrated the formation of mTOR-YY1 heterodimer induced by HG upregulated YY1, the nuclear translocation of which inactivated PGC-1α by binding to the PGC-1α promoter. Overexpression of YY1 induced mitochondrial dysfunctions in normal glucose cultured HK-2 cells and 8-week-old db/m mice. While, dysfunctional mitochondria induced by HG could be improved by knockdown of YY1. Finally, downregulation of YY1 could retard the progression of TIF by preventing mitochondrial functions, resulting in the improvement of epithelial-mesenchymal transition (EMT) in early DN. These findings suggested that YY1 was a novel regulator of mitochondrial function of RTECs and contributed to the occurrence of early DN-associated TIF .
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The data and material used and/or analyzed during the current study are available from the corresponding authors on reasonable request.
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Abbreviations
- YY1:
-
Yin Yang 1
- DN:
-
Diabetic nephropathy
- ESRD:
-
End-stage renal disease
- RTECs:
-
Renal tubular epithelial cells
- EMT:
-
Epithelial-mesenchymal transition
- TIF:
-
Tubulointerstitial fibrosis
- mTOR:
-
Mammalian target of rapamycin
- FBG:
-
Fasting blood glucose
- BUN:
-
Blood urea nitrogen
- HK-2:
-
Human proximal tubular epithelial cells
- HG:
-
High glucose
- NG:
-
Normal glucose
- α-SMA:
-
α-Smooth muscle actin
- E-ca:
-
E-cadherin
- ECM:
-
Extracellular matrix
- Cr:
-
Creatinine
- MA:
-
Mannitol
- Co-IP:
-
Co-immunoprecipitation
- ChIP:
-
Chromatin immunoprecipitation
- HIC:
-
Immunohistochemistry
- TEM:
-
Transmission electron microscopy
- MMP:
-
Mitochondrial membrane potential
- PGC-1α:
-
Peroxisome proliferator-activated receptor-γ coactlvator-1α
- TFAM:
-
Mitochondrial transcription factor A
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Funding
The work was supported by the National Natural Science Foundation of China (81973377, 81903689, and 82073906), the Key Natural Science Foundation of Jiangsu Higher Education Institutions of China (19KJA460008 and 19KJB350006), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the initializing Fund of Xuzhou Medical University (D2018011), and Postgraduate Research Practice Innovation Program of Jiangsu Province (No. KYCX21-2733, KYCX21-2735, and KYCX21-2736).
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The experiments of this work were designed by Qian Lu, Xiaoxing Yin, and Tingting Yang. The experiments were performed by Yinlu Hu, Shangxiu Chen, Lin Li, and Fanglin Shu. Tingting Yang and Yinlu Hu analyzed the data and wrote the manuscript. Tingting Yang, Yinlu Hu, and Sitong Qian edited the figures and tables. Tingting Yang, Qian Lu, and Xiaoxing Yin reviewed the manuscript. Rest of the authors either supplied reagent or helped in treatments to animal and cells. We thank Prof. Zhenzhou Jiang from China Pharmaceutical University for the article structural configuration.
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Tingting Yang and Yinlu Hu equally contributed to this work.
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• Mitochondrial dysfunction of RTECs was an earlier event in the pathological process of DN-associated TIF
• Up-regulated YY1 directly bound to PGC1-α promoter and suppresses its transcription in HG-cultured HK-2 cells
• The formation of mTOR-YY1 heterodimer up-regulated YY1 expression in vitro
• YY1 was critical for mitochondrial dysfunction of RTECs in vivo and in vitro
• YY1 knockdown improved renal function and blocked the emergence of TIF of db/db mice
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Yang, T., Hu, Y., Chen, S. et al. YY1 inactivated transcription co-regulator PGC-1α to promote mitochondrial dysfunction of early diabetic nephropathy-associated tubulointerstitial fibrosis. Cell Biol Toxicol 39, 391–413 (2023). https://doi.org/10.1007/s10565-022-09711-7
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DOI: https://doi.org/10.1007/s10565-022-09711-7