Abstract:

Ｏｂｊｅｃｔｉｖｅ：To investigate the protective effects of dabrafenib (DAB) on mouse renal ischemia reperfusion injury (IRI).
Ｍｅｔｈｏｄｏｌｏｇｙ：Mice were randomly divided into four groups (n=6) including sham group,IRI group,DAB group and dabrafenib preconditioning（DAB）+IRI group.Mice in sham group and DAB group received no treatment of IRI.Serum and kidney samples were collected 24 hours after IRI.The level of serum creatitine (SCr) and blood urea nitrogen (BUN) were measured.Renal injuries were evaluated by HE and PAS staining.The protein leves of NGAL and KIM1 were detected by Western Blot.The mRNA expressions of NGAL,KIM1,IL6 and TNFα were analyzed by qRTPCRThe expression of TNFα was observed by immunohistochemistry.Cell death was assessed by TUNELAnd the protein expressions of RIP1,RIP3,pRIP3,MLKL and pMLKL were detected by Western Blot.
Ｒｅｓｕｌｔｓ：Compared with sham group,SCr,BUN and renal damages were increased in IRI group(all P<005).Moreover,renal NGAL and KIM1 protein levels and mRNA expressions,IL6 、TNFα mRNA expressions and TNFα expression in renal tissue,RIP3,pRIP3,MLKL,pMLKL protein expressions were both upregulated(all P<005).In addition,TUNELpositive cells were more in IRI group.The effects of IRI were inhibited by dabrafenib.Compared to that in IRI group，dabrafenib precondition reversed IRIinduced damages of renal fuction and renal tissues,decreased the mRNA expressions of NGAL,KIM1,IL6 and TNFα,lowered the expression of TNFα in renal tissues,and reduced NGAL and KIM1 proteion levels(all P<005).Moreover,dabrafenib reduced TUNELpositive cells induced by IRI,together with RIP3、pRIP3 and pMLKL protein expressions(all P<005).However,RIP1 and MLKL protein levels had no changes between IRI and DAB+IRI group.All of the parameters above had no differences between sham and DAB group.
Ｃｏｎｃｌｕｓｉｏｎ：
Pretreatment with dabrafenib has protective effects on renal ischemia reperfusion injury of mice,which may be associated with inhibiting RIP3mediated necroptosis.

Key words: dabrafenib, renal ischemia reperfusion injury, necroptosis, RIP3