YY1 inactivated transcription co-regulator PGC-1α to promote mitochondrial dysfunction of early diabetic nephropathy-associated tubulointerstitial fibrosis.
Cell Biol Toxicol
; 39(2): 391-413, 2023 04.
Article
in En
| MEDLINE
| ID: mdl-35445903
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 ß 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 .
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetes Mellitus
/
Diabetic Nephropathies
Type of study:
Risk_factors_studies
Limits:
Animals
Language:
En
Journal:
Cell Biol Toxicol
Journal subject:
TOXICOLOGIA
Year:
2023
Document type:
Article
Affiliation country:
China
Publication country:
CH
/
SUIZA
/
SUÍÇA
/
SWITZERLAND