Role of TGF-ß1 in renal parenchymal scarring following childhood urinary tract infection

Abstract

Background. Significant variability exists in the outcome of renal parenchymal inflammation following urinary tract infection (UTI) in childhood as some children experience renal parenchymal scarring (RPS) while others do not scar. Since TGF-β1 is pro-fibrotic, we examined the role of this cytokine in RPS following UTI. Methods. Five polymorphisms of the TGF-β1 gene were investigated as well as the relationship between these polymorphisms and TGF-β1 production by peripheral blood mononuclear cells (PBMC) in vitro. DNA was isolated from 91 children shown to have developed RPS, 43 children with no evidence of scarring (NS) following UTI, and 171 healthy controls. Genotyping was performed by restriction fragment length polymorphism (RFLP). PBMC were isolated from a subgroup of 24 patients from the total population. Cells were stimulated with LPS + PMA + PHA and then TGF-β1 production was determined by ELISA. Results. Comparing the NS with the RPS group, there was an increase in the -800 GA genotypes (18.6 vs. 7.4%, P = 0.05; x2) and the Leu10→Pro CT (62.8 vs. 41.5%, P = 0.021), and a decrease in the -509 TT genotype (0.0 vs. 8.5%, P = 0.049). PBMC TGF-β1 production was higher in those patients with the -800 GG compared to those with a GA genotype stimulation index [stimulated/unstimulated TGF-β1 levels were 1.54 interquartile range (IQR) 1.42 to 1.75 vs. 1.19, IQR 0.94 to 1.51, P = 0.031]. Conclusions. There is an association between the TGF-β1 -800 GA, -509 TT and Leu10→Pro CT genotypes and the presence or absence of RPS. The low TGF-β1 producer status of the -800 GA genotype may protect against the development of a pro-fibrotic pathology.