Abstract
Primary causes of urinary tract obstruction that induces urine retention and results in hydronephrosis include uroliths, inflammation, and tumors. In this study, we analyzed the molecular pathology of ureteritis causing hydronephrosis in laboratory rodents.F2 progenies of C57BL/6 and DBA/2 mice were studied histopathologically and by comprehensive gene expression analysis of their ureters. Incidence of hydronephrosis was approximately 5% in F2 progenies. Histopathologically, this hydronephrosis was caused by stenosis of the proximal ureter, which showed fibrosis and papillary malformations of the proliferative epithelium with infiltrations of B-cell-dominated lymphocytes. Additionally, CD16-positive large granular leukocytes and eosinophils infiltrated from the ureteral mucosa to the muscular layer. Eosinophilic crystals were characteristically observed in the lumen of the ureter and the cytoplasm of large granular leukocytes, eosinophils, and transitional epithelial cells. Comprehensive gene profiling revealed remarkably elevated expression of genes associated with hyperimmune responses through activation of B cells in diseased ureters. Furthermore, diseased ureters showed dramatically higher gene expression of chitinase 3-like 3, known as Ym1, which is associated with formation both of adenomas in the transitional epithelium and of eosinophilic crystals in inflammatory conditions. The Ym1 protein was mainly localized to the cytoplasm of the transitional epithelium, infiltrated cells, and eosinophilic crystals in diseased ureters.We determined that the primary cause of hydronephrosis in F2 mice was ureteritis mediated by the local hyperimmune response with malformation of the transitional epithelium. Our data provide a novel molecular pathogenesis for elucidating causes of aseptic inflammation in human upper urinary tracts.
Highlights
In human clinical cases, aseptic inflammation in the upper urinary tracts, including the renal pelvis and the ureter, has been reported in diseases such as inflammatory pseudotumor (IPT) of the ureter, idiopathic segmental ureteritis (ISU), idiopathic retroperitoneal fibrosis involving the ureters (IRF), or eosinophilic ureteritis [1,2,3,4,5]
We report for the first time that the F2 progenies from inbred mice incidentally develop hydronephrosis subsequent to ureteritis with papillary malformations of the transitional epithelial cells (TECs) and infiltration of lymphocytes and eosinophils
The infiltrated CD16-positive cells were considered an NK cell or activated macrophage response to abnormal ureters. These inflammatory lesions characteristically contained eosinophils and granuloma was observed in several cases of F2 ureteritis. These pathological features overlap with aseptic inflammation in the upper urinary tract diagnosed as IPT of the ureter, ISU, IRF involving ureters, or eosinophilic ureteritis in humans [1,2,3,4,5]
Summary
Aseptic inflammation in the upper urinary tracts, including the renal pelvis and the ureter, has been reported in diseases such as inflammatory pseudotumor (IPT) of the ureter, idiopathic segmental ureteritis (ISU), idiopathic retroperitoneal fibrosis involving the ureters (IRF), or eosinophilic ureteritis [1,2,3,4,5]. Symptoms such as fever, abdominal pain, and hematuria and detection of an obstructed urinary tract on contrast radiography suggest the presence of these diseases [1]. To develop diagnostic methodology and novel therapy in addition to antiinflammatory symptomatic treatments, elucidation of the molecular pathology of aseptic inflammation is required
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