MiR-155 deficiency protects renal tubular epithelial cells from telomeric and genomic DNA damage in cisplatin-induced acute kidney injury.
Theranostics
; 12(10): 4753-4766, 2022.
Article
in En
| MEDLINE
| ID: mdl-35832084
ABSTRACT
Rationale Cisplatin nephrotoxicity is an important cause of acute kidney injury (AKI), limiting cisplatin application in cancer therapy. Growing evidence has suggested that genome instability, telomeric dysfunction, and DNA damage were involved in the tubular epithelial cells (TECs) damage in cisplatin-induced AKI (cAKI). However, the exact mechanism is largely unknown. Methods:
We subjected miR-155-/- mice and wild-type controls, as well as HK-2 cells, to cAKI models. We assessed kidney function and injury with standard techniques. The cell apoptosis and DNA damage of TECs were evaluated both in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization.Results:
The expression level of miR-155 was upregulated in cAKI. Inhibition of miR-155 expression protected cisplatin-induced AKI both in vivo and in vitro. Compared with wild-type mice, miR-155-/- mice had reduced mortality, improved renal function and pathological damage after cisplatin intervention. Moreover, inhibition of miR-155 expression attenuated TECs apoptosis and DNA damage. These protective effects were caused by increasing expression of telomeric repeat binding factor 1 (TRF1) and cyclin-dependent kinase 12 (CDK12), thereby limiting the telomeric dysfunction and the genomic DNA damage in cAKI.Conclusion:
We demonstrated that miR-155 deficiency could significantly attenuate pathological damage and mortality in cAKI through inhibition of TECs apoptosis, genome instability, and telomeric dysfunction, which is possibly regulated by the increasing expression of TRF1 and CDK12. This study will provide a new molecular strategy for the prevention of cAKI.Key words
Full text:
1
Collection:
01-internacional
Health context:
1_ASSA2030
/
6_ODS3_enfermedades_notrasmisibles
Database:
MEDLINE
Main subject:
DNA Damage
/
MicroRNAs
/
Acute Kidney Injury
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Theranostics
Year:
2022
Document type:
Article