Study On The Role That Methyl-CpG Binding Protein Mecp2 Plays In Acute Kidney Injury

Acute kidney injury(AKI)is defined by a rapid increase in serum creatinine,decrease in urine output,or both within a short time.As an acute kidney disease,AKI is associated with high morbidity and mortality,but effective treatments are still lacking at present.The patients incomplete recovery from AKI may subsequently develop chronic kidney disease,and eventually end-stage renal disease.Acute kidney injury can be caused by a variety of factors,including renal ischemia-reperfusion injury,drugs-induced nephrotoxicity or sepsis,etc.Renal ischemia-reperfusion injury is a major cause of AKI,and is a serious challenge during clinical renal transplantation and general cardiothoracic and cardiovascular surgery.Mecp2(Methyl-Cp G binding protein 2)is a critical epigenetic regulator,and its mutation or deletion is a major cause of a neurodevelopment disease called Rett syndrome.Notably,there are reports that some MECP2 mutant Rett syndrome patients or Mecp2-null Rett syndrome mice present urological dysfunctions;the Mecp2-null mice even died of kidney failure.However,it remains unclear whether and how Mecp2 affects AKI.In this thesis,we used wild type mice challenged with ischemia-reperfusion injury,renal tubular epithelial cells stimulated with in vitro hypoxia-reperfusion injury,and renal biopsy samples from AKI patients caused by kidney transplantation to study whether Mecp2 sensed AKI.The function of Mecp2 in ischemia-reperfusion injury was further studied in mice with specific Mecp2 deletion in renal tubules.Meanwhile,the effects of Mecp2 on Il-6/Stat3 signaling was studied by knockdown Mecp2 or overexpressing wild-type and different domain-deficient Mecp2 in cultured renal epithelial cells in vitro.Our results indicated rapidly upregulated Mecp2 protein level upon acute in vivo and in vitro renal injury,and the same phenomenon was observed in AKI patients.Furthermore,specific Mecp2 deletion in renal tubules aggravated ischemia-reperfusion injury,mainly manifested by aggravating renal tubular injury,renal cell apoptosis,inflammation and interstitial fibrosis.Mechanistically,Mecp2 directly bound to the promoter of proinflammatory cytokine Il-6 to negatively regulate its expression,thus inhibiting Stat3 activation,and this process depended on the transcriptional repression domain(TRD)of Mecp2.Together,our results revealed a novel protective role of Mecp2 against ischemia-reperfusion induced AKI via repressing the Il-6/Stat3 axis,and warranted further investigation on the prognosis and therapeutic potentials in AKI.