Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis
| Autor: | Chengguo Wei, Robert B. Colvin, Arjang Djamali, Jessica Overbey, Millagros Saminego, Ivy A. Rosales, Meng Ma, John Cijiang He, Huabao Xiong, Philip J. O'Connell, Christopher Woytovich, Zhengzi Yi, Zhengzhe Li, Wei Ding, Lorenzo Gallon, Rong Chen, Ilana Greene, Weijia Zhang, Bernd Schröppel, Madhav C. Menon, Y. Luan, Emilia Bagiella, Li Li, Peter Y. Chuang, Barbara Murphy |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Risk Transcriptional Activation Quantitative Trait Loci Gene Expression Renal function Biology Kidney Polymorphism Single Nucleotide Transforming Growth Factor beta1 Mice Chronic allograft nephropathy Fibrosis medicine Animals Humans Smad3 Protein Allele Genetic Association Studies beta Catenin Kidney transplantation Microfilament Proteins Kidney metabolism General Medicine Allografts medicine.disease Kidney Transplantation Molecular biology Introns Enhancer Elements Genetic HEK293 Cells medicine.anatomical_structure Genetic Loci Cancer research Kidney Diseases Disease Susceptibility Transcription Factor 7-Like 2 Protein Research Article Kidney disease |
| Zdroj: | Journal of Clinical Investigation. 125:208-221 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci76902 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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