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To discuss the application value of technologies such as chromosome microarray analysis (CMA) in fetuses with hydronephrosis and pyelectasis. Retrospectively collected the prenatal diagnostic data of 83 fetuses with hydronephrosis from January 2020 to July 2024. The positive rate of chromosomal abnormalities detected by different ultrasound abnormalities was statistically analyzed. Among the 83 pregnant women, 10 cases of abnormal karyotypes were detected by invasive prenatal diagnosis, with an abnormality rate of 12.05%. Numerical chromosomal abnormalities accounted for 90%, mainly trisomy 21 and 13. In the fetuses with normal karyotype/no abnormality, CMA additionally detected 15 copy number variations (CNVs) in 12 cases. Divided into isolated hydronephrosis and non-isolated hydronephrosis groups, the detection rates of fetuses carrying pathogenic CNVs were 5.56% and 12.77% respectively, and the detection rates of fetuses carrying variants of uncertain significance (VUS) were 19.44% and 8.51% respectively. Still, the differences between the two groups were not statistically significant (P > 0.05). Divided into moderate to severe hydronephrosis group and mild hydronephrosis group, the detection rate of pathogenic abnormalities by CMA was 10% and 37.21% respectively, and the difference between the two groups was statistically significant (P < 0.05). Hydronephrosis is associated with chromosomal abnormalities, and the rate of chromosomal abnormalities increases significantly as the degree of hydronephrosis increases. The combined use of CMA technology can detect abnormalities caused by chromosomal microdeletions and/or microduplications, which is of great value for clinical prenatal consultation.

NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress. Loss of Keap1 increases Nrf2 protein levels, and Keap1-null mice die of oesophageal hyperkeratosis because of Nrf2 hyperactivation. Here we show that deletion of oesophageal Nrf2 in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Renal tubular deletion of Keap1 promotes nephrogenic diabetes insipidus features, confirming that Nrf2 activation in developing tubular cells causes a water reabsorption defect. These findings suggest that Nrf2 activity should be tightly controlled during development in order to maintain renal homeostasis. In addition, tissue-specific ablation of Nrf2 in Keap1-null mice might create useful animal models to uncover novel physiological functions of Nrf2. Nrf2 regulates oxidative and electrophilic stress responses by modulating the expression of enzymes involved in detoxification pathways. Here Suzuki et al . show that Nrf2 activation in early tubular development promotes nephrogenic diabetes insipidus by regulating aquaporin 2 expression and trafficking and water permeability.

Over recent years routine ultrasound scanning has identified increasing numbers of neonates as having hydronephrosis and pelvi-ureteric junction obstruction (PUJO). This patient group presents a diagnostic and management challenge for paediatric nephrologists and urologists. In this review we consider the known molecular mechanisms underpinning PUJO and review the potential of utilising this information to develop novel therapeutics and diagnostic biomarkers to improve the care of children with this disorder.

Mowat-Wilson Syndrome (MWS) is an autosomal dominant genetic disorder caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 ( ZEB2 ) gene. Congenital anomalies of the kidney and urinary tract (CAKUT), including hydroureter and hydronephrosis, have been reported in patients with MWS. However, the role of the ZEB2 gene in urinary tract development and the cellular and molecular mechanisms underlying the CAKUT phenotypes in MWS remain unknown. In this study, we examined ZEB2 expression in the developing mouse ureter and generated Zeb2 ureteral mesenchyme-specific conditional knockout mice ( Zeb2 cKO) by crossing Zeb2 floxed mice with Tbx18 Cre + mice. The urinary tract of Zeb2 cKO mice and their wild-type littermates was analyzed for morphological and histological changes. Our results show that ZEB2 is expressed in TBX18 + ureteral mesenchymal cells during mouse ureter development. Deleting Zeb2 in these cells caused hydroureter and hydronephrosis, indicating obstructive uropathy. Cellular and molecular marker analysis revealed that the TAGLN + ACTA2 + ureteral smooth muscle cell (SMC) layer was absent in Zeb2 cKO mice. In contrast, the tunica adventitia cell layer was significantly expanded compared to controls. At the molecular level, Zeb2 cKO mice had significantly decreased TBX18 expression but increased SOX9 expression in the developing ureter compared to wild-type controls. Our findings demonstrate that ZEB2 is crucial for normal ureteral SMC differentiation during ureter development. Additionally, our study suggests that MWS patients may have abnormal ureteral SMC development, which contributes to the abnormalities of the urinary tract.

Obstructive hydronephrosis is caused by various factors such as chronic inflammation and tumors. Eosinophils and chitinase-like proteins (CLPs) are involved in the pathogenesis of hydronephrosis in mice; however, the specific mechanisms remain unknown. In this study, we morphologically analyzed a novel mouse model of obstructive hydronephrosis from onset to progression to clarify the effects of eosinophils and CLP on the development of hydronephrosis and tumorigenesis. The primary change was slight eosinophil infiltration of the ureteropelvic junction, even at 1 week of age, followed by a significant increase in CLP expression in the urothelium at 5 weeks of age, which led to proliferation of the urothelium. At 8 weeks of age, polyps with eosinophilic inflammation and urothelial hyperplasia expressing high levels of CLP formed at the ureteropelvic junction, leading to hydronephrosis. At 60 weeks of age, all mice with hydronephrosis exhibited chronic eosinophilic inflammation and adenomas that progressed to adenocarcinomas with high CLP expression. In summary, inflammation and epithelial proliferation at the ureteropelvic junction began with a single infiltration of eosinophils at the juvenile stage in mice. Eosinophilic inflammation is associated with the development of hydronephrosis and urothelial hyperplasia, which may progress to urothelial adenocarcinoma due to increased CLP expression.

Recent studies have reported conflicting findings regarding the significance of hydronephrosis (HN) in muscle-invasive bladder cancer (MIBC). The molecular characteristics of MIBC with HN are unclear, therefore, we aimed to address the gaps in previous research and elucidate HN's molecular significance in patients with MIBC. Clinical, genetic, and imaging information on bladder cancer patients enrolled in The Cancer Genome Atlas were obtained from public databases to analyze the association between the presence of hydronephrosis and genetic alterations and molecular subtyping. A total of 108 patients who underwent total cystectomy for MIBC at the Hiroshima University Hospital were enrolled in the study to verify the association between HN and renal function with patient prognosis. We observed a statistically significant difference in the distribution of molecular subtypes (p=0.0146). The proportion of patients with the luminal papillary subtype was approximately twice as high in patients with HN (48.8%) than in those without HN (25.0%). The mutation frequency of fibroblast growth factor receptor (FGFR) 3 was approximately three-fold higher in patients with HN (20.9%) than in those without HN (7.1%). Multivariate analysis, which considered HN and estimated glomerular filtration rate as confounding factors in our MIBC cohort, revealed that reduced renal function, but not HN, was an independent predictor for overall survival. MIBC presenting HN exhibits a high frequency of mutations in the FGFR3 gene. In addition, not HN itself, but reduced renal function due to HN may worsen the prognosis for MIBC.

Hydronephrosis, the dilation of kidneys due to abnormal urine retention, occurs spontaneously in certain inbred mouse strains. In humans, its occurrence is often attributed to acquired urinary tract obstructions in adults, whereas in children, it can be congenital. However, the genetic factors underlying hydronephrosis pathogenesis remain unclear. We investigated the cause of hydronephrosis by analyzing tetraspanin 7 (Tspan7) gene-modified mice, which had shown a high incidence of hydronephrosis-like symptoms. We found that these mice were characterized by low liver weights relative to kidney weights and elevated blood ammonia levels, suggesting liver involvement in hydronephrosis. Gene expression analysis of the liver suggested that dysfunction of ornithine transcarbamylase (OTC), encoded by the X chromosome gene Otc and involved in the urea cycle, may contribute as a congenital factor in hydronephrosis. This OTC dysfunction may be caused by genomic mutations in X chromosome genes contiguous to Otc, such as Tspan7, or via the genomic manipulations used to generate transgenic mice, including the introduction of Cre recombinase DNA cassettes and cleavage of loxP by Cre recombinase. Therefore, caution should be exercised in interpreting the hydronephrosis phenotype observed in transgenic mice as solely a physiological function of the target gene.

Structural birth defects in the kidney and urinary tract are observed in 0.5% of live births and are a major cause of end-stage renal disease, but their genetic aetiology is not well understood. Here we analyse 135 lines of mice identified in large-scale mouse mutagenesis screen and show that 29% of mutations causing congenital heart disease (CHD) also cause renal anomalies. The renal anomalies included duplex and multiplex kidneys, renal agenesis, hydronephrosis and cystic kidney disease. To assess the clinical relevance of these findings, we examined patients with CHD and observed a 30% co-occurrence of renal anomalies of a similar spectrum. Together, these findings demonstrate a common shared genetic aetiology for CHD and renal anomalies, indicating that CHD patients are at increased risk for complications from renal anomalies. This collection of mutant mouse models provides a resource for further studies to elucidate the developmental link between renal anomalies and CHD. Using forward genetic screen in fetal mice, Gregory Pazour and colleagues describe mutants affecting kidney/urinary tract development. The authors also show that mutants that cause kidney defects overlaps with those leading to congenital heart defects, thus linking renal anomalies and congenital heart disease.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by the arrest of fetal lung formation, resulting in neonatal death due to acute respiratory failure and pulmonary arterial hypertension. Heterozygous single-nucleotide variants or copy-number variant (CNV) deletions involving the FOXF1 gene and/or its lung-specific enhancer are found in the vast majority of ACDMPV patients. ACDMPV is often accompanied by extrapulmonary malformations, including the gastrointestinal, cardiac, or genitourinary systems. Thus far, most of the described ACDMPV patients have been diagnosed post mortem, based on histologic evaluation of the lung tissue and/or genetic testing. Here, we report a case of a prenatally detected de novo CNV deletion (~0.74 Mb) involving the FOXF1 gene in a fetus with ACDMPV and hydronephrosis. Since ACDMPV is challenging to detect by ultrasound examination, the more widespread implementation of prenatal genetic testing can facilitate early diagnosis, improve appropriate genetic counselling, and further management.

As a member of the cysteine protease family, cathepsin S (CTSS) serves an important role in diseases such as cancer, arthritis and atherosclerosis. Nevertheless, its role in renal fibrosis is unknown. In the present study, the effects of CTSS on renal fibrosis in mild (group M) and severe (group S) hydronephrosis were studied by reverse transcription-quantitative PCR (RT-qPCR), western blot analysis (WB), Masson's trichrome staining and immunohistochemical staining in mouse models. The effects of CTSS on extracellular matrix (ECM) deposition and epithelial-mesenchymal transition (EMT) and the potential mechanisms were further studied by RT-qPCR and WB in transforming growth factor (TGF-β1)-stimulated TCMK-1 cells. Compared with group N (no hydronephrosis), the expression levels of CTSS in the M and S groups were significantly higher, and a significant increase in ECM deposition was observed in the S group. In addition, compared with group N, the expression levels of TGF-β1, α-smooth muscle actin (α-SMA), SMAD2, SMAD3, phosphorylated (p)SMAD2 and pSMAD3 in groups M and S were significantly higher, whereas the expression of E-cadherin was significantly lower. Inhibition of CTSS expression increased the expression levels of TGF-β1, α-SMA, fibronectin, collagen-I, SMAD2, SMAD3, pSMAD2 and pSMAD3, whereas E-cadherin expression decreased. A significant increase in CTSS was observed in the TGF-β1-stimulated TCMK-1 cell line. ECM deposition and EMT were also intensified. The opposite outcomes occurred after intervention with small interfering RNA targeting CTSS. In conclusion, CTSS affected EMT and the deposition of ECM. CTSS may mediate the regulation of fibrosis by the TGF-β/SMAD signaling pathway. CTSS may serve an important role in the treatment of renal fibrosis.