Delayed onset of smooth muscle cell differentiation leads to hydroureter formation in mice with conditional loss of the zinc finger transcription factor gene Gata2 in the ureteric mesenchyme.

The establishment of the peristaltic machinery of the ureter is precisely controlled to cope with the onset of urine production in the fetal kidney. Retinoic acid (RA) has been identified as a signal that maintains the mesenchymal progenitors of the contractile smooth muscle cells (SMCs), while WNTs, SHH, and BMP4 induce their differentiation. How the activity of the underlying signalling pathways is controlled in time, space, and quantity to activate coordinately the SMC programme is poorly understood. Here, we provide evidence that the Zn-finger transcription factor GATA2 is involved in this crosstalk. In mice, Gata2 is expressed in the undifferentiated ureteric mesenchyme under control of RA signalling. Conditional deletion of Gata2 by a Tbx18cre driver results in hydroureter formation at birth, associated with a loss of differentiated SMCs. Analysis at earlier stages and in explant cultures revealed that SMC differentiation is not abrogated but delayed and that dilated ureters can partially regain peristaltic activity when relieved of urine pressure. Molecular analysis identified increased RA signalling as one factor contributing to the delay in SMC differentiation, possibly caused by reduced direct transcriptional activation of Cyp26a1, which encodes an RA-degrading enzyme. Our study identified GATA2 as a feedback inhibitor of RA signalling important for precise onset of ureteric SMC differentiation, and suggests that in a subset of cases of human congenital ureter dilatations, temporary relief of urine pressure may ameliorate the differentiation status of the SMC coat. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hnf1b and Pax2 cooperate to control different pathways in kidney and ureter morphogenesis.

The transcription factors HNF1B and Pax2, co-expressed in the Wolffian duct and ureteric bud epithelia, play essential roles during the early steps of mouse kidney development. In humans, heterozygous mutations in these genes display a number of common kidney phenotypes, including hypoplasia and multicystic hypoplastic kidneys. Moreover, a high prevalence of mutations either in HNF1B or PAX2 has been observed in children with renal hypodysplasia. To gain a better understanding of Hnf1b and Pax2 interactions in vivo, we generated compound heterozygous mice for Hnf1b and Pax2 null alleles. We show here that compound heterozygous mutants display phenotypes similar to severe congenital anomalies of the kidney and the urinary tract (CAKUT), including strong hypoplasia of the kidneys, caudal ectopic aborted ureter buds, duplex kidneys, megaureters and hydronephrosis. At a molecular level, compound mutants show a delay in nephron segment and medullar interstitial differentiation, increased apoptosis and a transient decrease in Lim1 and Wnt4 expression. We also observe a perturbation of smooth muscle differentiation around the ureter associated with a local down-regulation in transcript levels of Bmp4 and Tbx18, two key regulators involved in ureter smooth muscle formation, thus explaining, at least in part, megaureters. These results together uncover a novel role of Hnf1b as a modifier of the Pax2 haplo-insufficient phenotype and show that these two transcription factors operate in common pathways governing both kidney morphogenesis and ureter differentiation. This mouse model should provide new insights into the pathogenic mechanisms of human CAKUT, the most frequent developmental defect identified in newborns.

Antiteratogenic effects of alpha-naphthoflavone on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed mice in utero.

The effects of alpha-naphthoflavone, an aryl hydrocarbon receptor (AhR) antagonist, on the reproductive toxicity and teratogenicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were investigated. Pregnant C57BL/6J mice were orally administered alpha-naphthoflavone either once on gestational day 12 (GD12; 50 microg/kg) or for 6 days (GD8-GD13; 5 mg/kg/day) followed by an oral challenge with TCDD (14 microg/kg) on GD12. Cesarean section was performed on GD18 for the evaluation of maternal and fetal toxicities. TCDD caused severe fetal malformations including cleft palate (43.7%) and renal pelvic and ureteric dilatations (100%). The administration of alpha-naphthoflavone either in a single treatment or 6-days remarkably reduced the incidence of cleft palate to 27.6% and 26.5%, respectively. In addition, the degree of renal pelvic and ureteric dilatations caused by TCDD were significantly attenuated by repeated treatment of alpha-naphthoflavone. These results suggest that AhR antagonists such as alpha-naphthoflavone could be promising candidates for reducing the incidence and severity of fetal malformations caused by TCDD exposure in utero.

Effects of transforming growth factor on the developing embryonic ureter: An in-vitro megaureter model in mice.

INTRODUCTION: It is generally agreed that the cause of a megaureter is narrowing at the vesicoureteral junction, with a functional obstruction arising from an aperistaltic, juxtavesical segment that is unable to transport urine at an acceptable rate. Histological examinations of megaureter specimens have reported several histological analyses, and the pathogenic role of transforming growth factor is still a matter of speculation. OBJECTIVE: To evaluate whether transforming growth factor-beta (TGF-ß) and its receptors (TGFRs) are expressed during ureterovesical junction (UVJ) and lower ureter development in mice, and whether exogenous TGF-ß might postpone the maturation of smooth muscle cells, in the pathogenesis of megaureter using an embryonic organ-culture model. METHODS: Expression of TGF-ß and TGFRs on the lower ureter and UVJ were determined at different embryonic days (E) (E16, 18, 20 and postnatal day 1). The functional studies were performed by harvesting ureters from wild-type mice at embryonic day 16 (E16), which were grown in serum-free organ-culture; some cultures were supplemented with TGF-ß (2 and 20 ng/ml) and/or with soluble TGFR, which blocks bioactivity. Organs were harvested after 6 days and the expression of CD31 and Ki67 were assessed using immunohistochemistry. The muscle content of the UVJ and ureter were analyzed by flowcytometry. RESULTS: The TGF-ß and TGFR positive cells were immune detected in embryonic ureters. The TGF-ß expression was highest on E18 and decreased postnatally. Exogenous TGF-ß decreased ureterovesical (UV) muscle differentiation and proliferation. The longitudinal muscle fibers were significantly less in TGF-ß explants. The TGF-ß also decreased the proportions of cells expressing α smooth muscle actin (α-SMA). Soluble TGFR blocked the effects of exogenous TGF-ß. CONCLUSIONS: In organ culture, exogenous TGF-ß postpones the UV smooth muscle proliferation and affects the muscular structure. Whether the effects of TGF-ß are direct or indirect, these form an in-vitro megaureter model. The finding that TGF-ß is highest in embryonic ureters in vivo and decreased postnatally suggests that a pathological persistence might potentially explain the pathogenesis of primary megaureters.

Congenital ureteric cyst--rare anomaly.

A rare example of a congenital cyst of the ureter is described and the embryologic development of the abnormality discussed. The world literature relevant to the case is reviewed.

Ectopic ureterocele, hydroureter, and renal dysplasia: an embryogenic triad.

A review of the literature of the embryogenesis of ectopic ureterocele is presented. A theory linking the triad of ectopic ureterocele, hydroureter, and renal dysplasia to a primary intrinsic developmental abnormality of size and position of the ureteral bud is postulated.

Abnormalities of the ureteral bud.

The development and incorporation of the ureteric bud into the developing bladder is a complex process, and it is influenced by events occurring at the same time in the development of other systems in the perineum. Knowledge of the embryology of the ureteric bud and associated wolffian duct is the key to understanding the development of the entire genitourinary system. If the normal embryology is understood, the dysembryogenesis that results in many of the common anomalies of the lower urinary system is simplified. Many of the concepts proposed in this discussion are well substantiated, others are more difficult to prove conclusively. It is believed, however, that the embryologic approach provides a simplified understanding of many of the common problems encountered in pediatric urology. The key in clinical practice to the diagnosis and understanding of these defects is the cystoscopic examination. Careful assessment of the orifice's position, appearance, and tunnel length will allow the interpretation of how the abnormality came about, and also provides valuable information concerning the state of the associated renal segment. This in turn allow better therapeutic management of the problem based on the knowledge of the severity of the renal anomaly associated with the abnormality found in the bladder.

Embryology, anatomy, and surgical applications of the kidney and ureter.

This article discusses the embryology and anatomy of the kidney and ureter. Surgical approaches, such as the lumbar and thoracoabdominal, are provided. Operations for kidney (i.e., radical nephrectomy, nephroureterectomy, and partial nephrectomy) and ureteric tumors also are discussed.

Experimental ureterohydronephrosis in fetal rats.

This study tests the hypothesis that prenatal exposure to 2,4-dichlorophenyl-p-nitrophenyl ether (nitrofen), an herbicide known to induce pulmonary hypoplasia and other malformations in fetal rats, also may induce ureterohydronephrosis (UHN) and oligohydramnios. Time-dated pregnant Wistar rats were given 100 mg of the chemical on day 9 or 11 of gestation, and the findings in their fetuses were compared with those of suitable controls. Marked bilateral UHN was found in the majority of exposed fetuses, but without evidence of either mechanical obstruction or dysplastic parenchymal lesions. These animals had various degrees of lung hypoplasia. The amount of fluid in their amniotic sacs was increased rather than decreased and it was independent of lung weight but correlated to some extent with UHN grade. Urinary tract dilatation and polyhydramnios in this model most likely are attributable to polyuria caused by nitrofen-induced impairment of renal concentrating capacity. This relatively simple animal model might facilitate research into some aspects of the physiology of nonobstructive, prenatally dilated urinary tracts.

Pathology of ureterorenal units in various ureteral anomalies with particular reference to the genesis of renal dysplasia.

Renal morphology of various congenital ureteral anomalies was investigated to gain further insight into the genesis of associated renal dysplasia. Abnormality in the ureteral bud explains the genesis of renal dysplasia as long as the adjoining ureter is cranially ectopic. In caudal ectopy of either single or duplex system, no difference was found in the histologic quality of kidneys with G and H position orifice. In the single system kidneys of H position orifice, however, occurrence of renal dysplasia was not associated with obstruction, suggesting the operation of the "bud theory" even in single system caudal ectopy. In anomalies in which the ureteral orifice was not ectopic, it was suggested that renal parenchymal development was impaired by complete, but not by incomplete obstruction. The association of dysplastic ureter and renal dysplasia was not so frequent as anticipated and the hypodysplastic values of the kidneys with and without dysplastic ureters were similar, suggesting no direct causal relationship between them.

Agenesis of kidney associated with malformations of the seminal vesicle. Various clinical presentations.

Ureteral seminal vesicle anomaly associated with ipsilateral renal agenesis is a rare occurrence. Cystic anomaly of the seminal vesicle may be asymptomatic or discovered by rectal examination and cystoscopy for evaluation of bladder irritative symptoms, perineal and testicular pain, ejaculatory disturbances and rarely infertility. The condition was diagnosed in three patients with various clinical presentations.

Paraureteral diverticula: clinical experience with 17 cases with associated renal dysmorphism.

We report our experience with 17 cases of paraureteral diverticula seen in the last 12 years. These 17 cases represent a particular group of patients with ureteral reflux in that they often had ureteral obstruction too. Early operative intervention is recommended. There is a trend towards renal dysmorphism and dysplasia as the position of the ureteral orifice laterlizes in the diverticulum. A paraureteral diverticulum was considered to be the developmental extravesical expansion of the terminal ureteral end by virtue of the caudally positioned ureteral bud in the wolffian duct.

Embryogenesis of ureteral anomalies: a unifying theory.

Extensive gross, microscopic and clinical studies of various ureteral anomalies have enabled investigators to set forth theories regarding the aetiologies of these anomalies consistent with observed fact. Synthesis of these observations allows for a simplified classification of mega-ureter (primary obstructed, reflux and non-obstructed, non-reflux mega-ureters), ureterocele, duplex ureters and ectopic ureters based upon some combination of mesenchymal differentiation anomalies and location anomalies. A defect early in mesenchymal differentiation would be expected to result in panureteral disease. A defect later in development would result in a focal abnormality anywhere along the course of the ureter. Influence upon ureteral bud mesenchyme by local expansion factors in the bladder base may result in various types of ureterocele. Position of the ureteral orifice on the trigone or in Wolffian duct derivatives would occur in accordance with the Weigert-Meyer principle and would correlate with upper tract dysplasias. Thus, an attempt has been made to systematize and trace the origins of mega-ureter, ureterocele, duplex ureters and ectopic ureters to defects of differentiation of the basic mesoblastic cell in aberrant locations of the ureteral bud.

Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology.

The Society for Fetal Urology (SFU) was founded in 1988 to study the postnatal evolution of prenatally detected anomalies of the urinary tract by following those neonates whose prenatal studies have brought them to medical attention while asymptomatic. The SFU has attempted to standardize methods of performing and grading the ultrasound and radionuclide examinations in this population. A system to grade upper tract dilatation or hydronephrosis (HN) imaged by ultrasound has been developed and is being used by SFU members in 36 institutions. The appearance of the calices, renal pelvis and renal parenchyma are key in determining the grade of HN and are illustrated in this article.

The vesicoureteral hiatus and paraureteral diverticula.

Two ureteral sheaths and the vesical musculature combine to form a watertight ureterovesical junction but the precise anatomy and function of each component are still somewhat contentious. The morphology was studied in postmortem specimens of children with and without paraureteral diverticula and urethral obstruction, and function by deductive reasoning from radiographic and surgical observations in living children. Waldeyer's fascia (the superficial sheath) of the ureter was found to seal the potential space between the tunnel wall and the ureter, and deficiencies were associated with hiatal hernias. The deep sheath provided anchorage of the ureter to the trigone and through the attachments of the superficial sheath to the bladder wall. Both sheaths and the tunnel muscles could be identified clearly and dissected precisely at operations involving the ureterovesical junction to facilitate the surgical procedures.

Paraureteral diverticula. Associated renal morphology and embryogenesis.

A study was made of paraureteric diverticula, the associated ureteric orifices, and the accompanying kidneys. It was shown that the kidney was more abnormal as the ureteric orifice position lay more laterally and into the diverticulum. The fascial arrangements of the terminal ureter and the related diverticulum were examined. When the ureter opened totally within the diverticulum, both structures showed a single investment of fascia, suggesting a common embryologic orgin of the two structures. When the ureter opened either separately into the bladder or on the verge of the diverticulum, the urter and the adjacent diverticulum each had separate fascial investment, suggesting a different etiology for the formation of this type of diverticulum. A total of 25 single-system specimens were employed for the above study. In the series there were an additional three duplex systems associated with paraureteric diverticula in shich the kidney morphology followed the above pattern but the fascial arrangements were different. Based on the observations of this investigation, it is suggested that the renal morphology is governed by the position of the ureteric orifice in the diverticulum and that the term vesical hiatal diverticula be used to denote those diverticula occurring in the vicinity of the ureteric orifice. It is further suggested that the diverticulum which engulfs the ureteric orifice be called paraureteral, and those with separate orifices in the bladder be termed periureteral to differentiate the embryologic from the pulsion etiologies.