Risk factor for renal allograft fibrosis

Patients with chronic kidney disease (CKD) and kidney transplant recipients with chronic allograft nephropathy (CAN) lose renal function due to progressive fibrosis. A SNP within the gene encoding the PDZ domain-containing protein SHROOM3 is associated with CKD; however, the presence of this SNP has not been evaluated in CAN development. Madhav Menon and colleagues at the Icahn School of Medicine at Mount Sinai evaluated the presence of the CKD-associated SHROOM3 polymorphism in a prospective cohort of renal allograft recipients and determined that the presence of the CKD-associated allele in the donor kidney increased SHROOM3 expression in the allograft. Moreover, the associated increase in SHROOM3 expression in the transplanted kidney correlated with a greater risk of kidney dysfunction and increased fibrosis at 12 months post-transplant. In renal tubular cells, SHROOM3 enhanced canonical TGF-β1/SMAD3 signaling, resulting in increased expression of profibrotic genes. Renal-specific knockdown or deletion of Shroom3 in the unilateral ureteric obstruction (UUO) mouse model abrogated kidney fibrosis. The results of this study reveal that SHROOM3 expression exacerbates renal fibrosis and suggest that targeting SHROOM3 has potential to prevent kidney fibrosis and CAN. The accompanying image shows picrosirius red staining, which indicates collagen deposition, of UUO kidney sections from WT animals (right) and Shroom3 knockdown animals. 

Published December 1, 2014, by Corinne Williams

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Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis
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Published January 2, 2015; First published December 1, 2014
Citation Information: J Clin Invest. 2015;125(1):208-221. https://doi.org/10.1172/JCI76902.
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Research Article Nephrology

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

Madhav C. Menon, Peter Y. Chuang, Zhengzhe Li, Chengguo Wei, Weijia Zhang, Yi Luan, Zhengzi Yi, Huabao Xiong, Christopher Woytovich, Ilana Greene, Jessica Overbey, Ivy Rosales, Emilia Bagiella, Rong Chen, Meng Ma, Li Li, Wei Ding, Arjang Djamali, Millagros Saminego, Philip J. O’Connell, Lorenzo Gallon, Robert Colvin, Bernd Schroppel, John Cijiang He, Barbara Murphy

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