miRNA-21 ablation protects against liver injury and necroptosis in cholestasis.
Marta B AfonsoPedro M RodriguesAndré L SimãoMaria M GasparTânia CarvalhoPaula BorralhoJesús M BañalesRui E CastroCecília M P RodriguesPublished in: Cell death and differentiation (2017)
Inhibition of microRNA-21 (miR-21) prevents necroptosis in the mouse pancreas. Necroptosis contributes to hepatic necro-inflammation in the common bile duct ligation (BDL) murine model. We aimed to evaluate the role of miR-21 in mediating deleterious processes associated with cholestasis. Mechanistic studies established a functional link between miR-21 and necroptosis through cyclin-dependent kinase 2-associated protein 1 (CDK2AP1). miR-21 expression increased in the liver of primary biliary cholangitis (PBC) patients and BDL wild-type (WT) mice at both 3 and 14 days. Notably, under BDL, miR-21 -/- mice displayed decreased liver injury markers in serum compared with WT mice, accompanied by reduced hepatocellular degeneration, oxidative stress and fibrosis. Hallmarks of necroptosis were decreased in the liver of BDL miR-21 -/- mice, via relieved repression of CDK2AP1. Further, miR-21 -/- mice displayed improved adaptive response of bile acid homeostasis. In conclusion, miR-21 ablation ameliorates liver damage and necroptosis in BDL mice. Inhibition of miR-21 should arise as a promising approach to treat cholestasis.
Keyphrases
- cell proliferation
- long non coding rna
- liver injury
- long noncoding rna
- drug induced
- oxidative stress
- wild type
- poor prognosis
- cell cycle
- high fat diet induced
- transcription factor
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- adipose tissue
- peritoneal dialysis
- ischemia reperfusion injury
- protein kinase
- atrial fibrillation
- heat shock
- tyrosine kinase