We reasoned that the settng of AK, actvated B catenmght also drec

We reasoned the settng of AK, actvated B catenmght also drectly handle the transcrptoof pro survval genes.that regards, prevous studes ndcate that survvn, a member in the nhbtors of apoptoss protens famy that promotes cell survval by preventng apoptoss,28, 29 s a drect downstream target gene of B catenn.30, 31hence, we examned survvmRNA expressothe kdneys by quanttatve, genuine tme RT PCR.As showFgure 6e, the steady state amount of survvmRNA KsB cat mce at two days after folc acd njectowas sgnfcantly reduced thathat the controls.All collectively, as lustrated Fgure 6f, t gets clear that loss of B catenstmulates multple sgnalng hop over to this site pathways leadng to tubular cell apoptoss following AK.Loss of tubular B catenalso aggravates AK nduced by schema reperfusonjury We also nvestgated the cytoprotectve role of endogenous B catenby utzng a different model of AK, renal schema reperfusonjury.At one day immediately after R, all handle mce survved, whe one out of 4 KsB cat mce ded.
As showFgure 7a, serum creatnne levels at 1 day right after R had been sgnfcantlyhgher KsB cat mce thathat the controls.KsB supplier PF-00562271 cat kdneys also showed more serious morphologcal njury, characterzed by reduction of brush border and tubular cell reduction.Smarly, TUNEL stanng also exhbted a lot more apoptoss the kdneys soon after R KsB cat mce thathat the controls.Renal expressoof Bax protewas markedly ncreased the kdneys of KsB cat mce at one day following R, in contrast towards the controls.quick, these results ndcate that reduction of endogenous B catenexacerbates schemc AK as well.Actvatoof B catenprotects tubular cells aganst apoptoss vtro To provde drect evdence that lnks the loss of B catento tubular cell apoptoss, we fnally nvestgated the potental function of B catenactvatoregulatng tubular cell survval soon after njury by usng vtro method.For actvatng endogenous B catenn,humaproxmal tubular epthelal cells have been transfected wth the expressovector encodng Wnt1, the prototype member of Wnt famy that actvates B catenva canoncal pathway.Prevous studeshave showthat ectopc expressoof Wnt1 leads to endogenous B catenactvatoHKC eight cells.
32 As showFgure eight, a and b, sgnfcant apoptoss was observed HKC eight cells just after treatment wth staurosporne, a potent apoptoss nducer,33, 34 to get a brief perod of ncubaton, as lustrated by TUNEL stanng.on the other hand, transfectoof Wnt1 expressovector wholly protectedhKC 8 cells from STS nduced apoptoss under very same condtons.Wnt1 also nduced survvmRNA expressotubular epthelal cells, as demonstrated by qRT PCR.As showFgure 8d, tubular cell

apoptoss nduced by STS was assocated wth Bax nductoHKC 8 cells.even so, ectopc expressoof Wnt1 substantally abolshed Bax nductoHKC eight cells.Consstent wth the vvo data, actvatoof endogenous B catenby Wnt1 also promoted Akt phosphorylatoand nhbted p53 expressotubular cells after njury.Smarly, ectopc expressoof exogenous B catenby transfectng ofhKC eight cells wth termnally truncated, stabzed B catenexpressovector also prevented STS nduced apoptoss, nduced survvmRNA expressoand abolshed Bax nducton.

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