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Updated: Apr 20, 2026
Mouse Kidney Transplantation: Models of Allograft Rejection
Published on: October 11, 2014
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.
Insights
A specific gene variant (rs17319721) in the SHROOM3 gene, found in kidney donors, increases fibrosis in transplant recipients. This variant enhances SHROOM3 expression, promoting kidney allograft injury and loss of function.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Fibrosis is a key factor in kidney function loss for chronic kidney disease (CKD) patients and kidney transplant recipients with chronic allograft nephropathy (CAN).
- A single nucleotide polymorphism (SNP) in the SHROOM3 gene (rs17319721) has been previously associated with CKD.
Purpose of the Study:
- To investigate the impact of the intronic SHROOM3 SNP (rs17319721) on the development of CAN in a prospective cohort of renal allograft recipients.
- To elucidate the molecular mechanisms by which this SHROOM3 variant influences allograft fibrosis and renal function.
Main Methods:
- Prospective cohort study of renal allograft recipients.
- Analysis of donor SHROOM3 genotype (rs17319721) and its correlation with allograft SHROOM3 expression.
- In vitro studies using renal tubular cells to determine the functional role of the risk allele in SHROOM3 transcription.
- Investigation of the interplay between SHROOM3, TGF-β1 signaling, and collagen expression.
- In vivo studies using mouse models with unilateral ureteric obstruction to assess the effect of Shroom3 knockdown on interstitial fibrosis.
Main Results:
- The presence of the rs17319721 risk allele in the donor correlated with increased SHROOM3 expression in the allograft.
- The risk allele functions as a TCF7L2-dependent enhancer, increasing SHROOM3 transcription.
- SHROOM3 facilitates canonical TGF-β1 signaling and upregulates collagen (COL1A1) expression in renal tubular cells.
- Knockdown of Shroom3 significantly reduced interstitial fibrosis in a mouse model.
- Donor SHROOM3 risk allele and higher allograft SHROOM3 expression at 3 months post-transplant were associated with increased fibrosis and reduced estimated glomerular filtration rate (eGFR) at 12 months.
Conclusions:
- The rs17319721 SNP in SHROOM3 acts as a cis-acting expression quantitative trait locus, influencing SHROOM3 transcription.
- This genetic variation promotes kidney allograft fibrosis by enhancing TGF-β1 signaling and collagen production.
- The SHROOM3 risk allele is a significant contributor to allograft injury and subsequent decline in renal function in transplant recipients.
