title: Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis.
abstract: Fibrosis underlies the loss of renal function in patients with chronic kidney disease (CKD) and in kidney transplant recipients with chronic allograft nephropathy (CAN). Here, we studied the effect of an intronic SNP in SHROOM3, which has previously been linked to CKD, on the development of CAN in a prospective cohort of renal allograft recipients. The presence of the rs17319721 allele at the SHROOM3 locus in the donor correlated with increased SHROOM3 expression in the allograft. In vitro, we determined that the sequence containing the risk allele at rs17319721 is a transcription factor 7-like 2-dependent (TCF7L2-dependent) enhancer element that functions to increase SHROOM3 transcription. In renal tubular cells, TGF-β1 administration upregulated SHROOM3 expression in a β-catenin/TCF7L2-mediated manner, while SHROOM3 in turn facilitated canonical TGF-β1 signaling and increased α1 collagen (COL1A1) expression. Inducible and tubular cell-specific knockdown of Shroom3 markedly abrogated interstitial fibrosis in mice with unilateral ureteric obstruction. Moreover, SHROOM3 expression in allografts at 3 months after transplant and the presence of the SHROOM3 risk allele in the donor correlated with increased allograft fibrosis and with reduced estimated glomerular filtration rate at 12 months after transplant. Our findings suggest that rs17319721 functions as a cis-acting expression quantitative trait locus of SHROOM3 that facilitates TGF-β1 signaling and contributes to allograft injury.
authors.forename: Madhav C
authors.initials: MC
authors.lastname: Menon
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Chuang
authors.forename: Zhengzhe
authors.initials: Z
authors.lastname: Li
authors.forename: Chengguo
authors.initials: C
authors.lastname: Wei
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Luan
authors.forename: Zhengzi
authors.initials: Z
authors.lastname: Yi
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.forename: Christopher
authors.initials: C
authors.lastname: Woytovich
authors.forename: Ilana
authors.initials: I
authors.lastname: Greene
authors.forename: Jessica
authors.initials: J
authors.lastname: Overbey
authors.forename: Ivy
authors.initials: I
authors.lastname: Rosales
authors.forename: Emilia
authors.initials: E
authors.lastname: Bagiella
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Meng
authors.initials: M
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Arjang
authors.initials: A
authors.lastname: Djamali
authors.forename: Millagros
authors.initials: M
authors.lastname: Saminego
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.forename: Robert
authors.initials: R
authors.lastname: Colvin
authors.forename: Bernd
authors.initials: B
authors.lastname: Schroppel
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.forename: Barbara
authors.initials: B
authors.lastname: Murphy
mesh_terms: D064591:Allografts; D000818:Animals; D004198:Disease Susceptibility; D004742:Enhancer Elements, Genetic; D005355:Fibrosis / Q000378:metabolism; D015870:Gene Expression; D056726:Genetic Association Studies; D056426:Genetic Loci; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012306:Risk; D051900:Smad3 Protein / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000502:physiology; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
chemical_list: C495270:CTNNB1 protein, human; D008840:Microfilament Proteins; C000596976:SHROOM3 protein, human; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C544894:TCF7L2 protein, human; C508960:TGFB1 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D053773:Transforming Growth Factor beta1; D051176:beta Catenin