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.
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
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