Ureteropelvic junction obstruction (UPJO) is a leading cause of congenital hydronephrosis. Its etiology is associated with dysregulated extracellular matrix (ECM) remodeling and epithelial-mesenchymal transition (EMT). While Hepatocyte Growth Factor (HGF) is a known antagonist of fibrosis in other organs, its role in human UPJO pathogenesis remains unexplored. Stenotic ureteropelvic junction (UPJ) tissues from pediatric UPJO patients (n = 40) and normal ureteral tissues from duplex kidney controls (Ctrl, n = 10) were obtained in our hospital. Analyses included demographic and clinical characteristics, immunohistochemistry (IHC), quantitative real-time PCR (qPCR), and Western blotting (WB) to assess HGF, fibrosis markers (Col1a1, Fibronectin 1 FN1, α-smooth muscle actin α-SMA), and EMT markers (E-cadherin, N-cadherin, β-catenin, Vimentin). In vitro studies used TGFβ-stimulated human ureteral epithelial cells (SV-HUC-1) ± HGF co-treatment to evaluate fibrosis, EMT, and cell migration (scratch assay). The UPJO group was characterized by a significant male predominance, more severe hydronephrosis as evidenced by larger renal pelvic diameter and higher Society of Fetal Urology (SFU) grade, and comparable age and weight to the Ctrl group. IHC, qPCR, and WB revealed significant downregulation of HGF and the epithelial marker E-cadherin, alongside marked upregulation of fibrosis markers (Col1a1, FN1, α-SMA) and mesenchymal markers (N-cadherin, β-catenin, Vimentin) in stenotic UPJ tissues versus Ctrls. In vitro, HGF co-treatment significantly attenuated TGFβ-induced upregulation of fibrotic markers (Col1a1, FN1, α-SMA), EMT (reversal of E-cadherin downregulation and N-cadherin/β-catenin/Vimentin upregulation), and enhanced SV-HUC-1 cell migration. This study provides the first clinical evidence of HGF downregulation at stenotic UPJ segments in UPJO patients, correlating with elevated fibrosis and EMT markers. These findings implicate impaired HGF signaling in UPJO pathogenesis and position HGF as a promising therapeutic target for mitigating fibrotic obstruction.
Lin et al. (Sat,) studied this question.