Homozygous WNT9B variants in two families with bilateral renal agenesis/hypoplasia/dysplasia.

WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. To our knowledge, WNT9B has not been associated with renal defects in humans; however, WNT9B-/- mice have renal agenesis/hypoplasia and reproductive tract abnormalities. We report four individuals from two unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 has bilateral renal cystic dysplasia and chronic kidney disease. He has two deceased siblings who presented with bilateral renal hypoplasia/agenesis. The three affected family members were homozygous for a missense variant in WNT9B (NM_003396.2: c.949G>A/p.(Gly317Arg)). The proband from Family 2 has renal hypoplasia/dysplasia, chronic kidney disease, and is homozygous for a nonsense variant in WNT9B (NM_003396.2: c.11dupC/p.(Pro5Alafs*52)). Two of her siblings died in the neonatal period, one confirmed to be in the context of oligohydramnios. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance. We propose a novel association of WNT9B and renal anomalies in humans. Further study is needed to delineate the contribution of WNT9B to genitourinary anomalies in humans.

Sprouty1 Controls Genitourinary Development via its N-Terminal Tyrosine.

BACKGROUND: Studies in mice suggest that perturbations of the GDNF-Ret signaling pathway are a major genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT). Mutations in Sprouty1, an intracellular Ret inhibitor, results in supernumerary kidneys, megaureters, and hydronephrosis in mice. But the underlying molecular mechanisms involved and which structural domains are essential for Sprouty1 function are a matter of controversy, partly because studies have so far relied on ectopic overexpression of the gene in cell lines. A conserved N-terminal tyrosine has been frequently, but not always, identified as critical for the function of Sprouty1 in vitro. METHODS: We generated Sprouty1 knockin mice bearing a tyrosine-to-alanine substitution in position 53, corresponding to the conserved N-terminal tyrosine of Sprouty1. We characterized the development of the genitourinary systems in these mice via different methods, including the use of reporter mice expressing EGFP from the Ret locus, and whole-mount cytokeratin staining. RESULTS: Mice lacking this tyrosine grow ectopic ureteric buds that will ultimately form supernumerary kidneys, a phenotype indistinguishable to that of Sprouty1 knockout mice. Sprouty1 knockin mice also present megaureters and vesicoureteral reflux, caused by failure of ureters to separate from Wolffian ducts and migrate to their definitive position. CONCLUSIONS: Tyrosine 53 is absolutely necessary for Sprouty1 function during genitourinary development in mice.

Intrauterine low-protein diet disturbs metanephric gene expression and induces urinary tract developmental abnormalities in mice.

Intrauterine low-protein diet can affect kidney development and hence final nephron number. In this study, we reported that intrauterine low-protein diet can cause congenital anomalies of the kidney and urinary tract (CAKUT) phenotypes, which was dominated by the duplicated collecting system phenotype. At the same time, ectopic ureteric buds were increased under intrauterine low-protein diet and the number of UB branches was reduced in the serum-free culture. Intrauterine low-protein diet can change metanephric gene expression. Slit2/Robo2 and Spry1 expression levels were decreased, Ret expression was increased, and downstream p-Akt activity enhanced with apoptosis abnormal in ureteric bud tissue, which may be the mechanisms that intrauterine low-protein diet causes increased incidence of CAKUT in offspring. Thus, we showed correlation between intrauterine low-protein diet and CAKUT in offspring.

Histology Atlas of the Developing Mouse Urinary System With Emphasis on Prenatal Days E10.5-E18.5.

Congenital abnormalities of the urinary tract are some of the most common human developmental abnormalities. Several genetically engineered mouse models have been developed to mimic these abnormalities and aim to better understand the molecular mechanisms of disease. This atlas has been developed as an aid to pathologists and other biomedical scientists for identification of abnormalities in the developing murine urinary tract by cataloguing normal structures at each stage of development. Hematoxylin and eosin- and immunohistochemical-stained sections are provided, with a focus on E10.5-E18.5, as well as a brief discussion of postnatal events in urinary tract development. A section on abnormalities in the development of the urinary tract is also provided, and molecular mechanisms are presented as supplementary material. Additionally, overviews of the 2 key processes of kidney development, branching morphogenesis and nephrogenesis, are provided to aid in the understanding of the complex organogenesis of the kidney. One of the key findings of this atlas is the histological identification of the ureteric bud at E10.5, as previous literature has provided conflicting reports on the initial point of budding. Furthermore, attention is paid to points where murine development is significantly distinct from human development, namely, in the cessation of nephrogenesis.

Mutations in DSTYK and dominant urinary tract malformations.

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. CONCLUSIONS: We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

Evolution of a novel developmental trajectory: fission is distinct from regeneration in the annelid Pristina leidyi.

Understanding how novelty arises has been a major focus of evolutionary developmental biology. While the origin of new genes, gene functions, and morphological features has been studied intensely, the origin of entire developmental trajectories, such as regeneration or agametic reproduction, remains poorly understood. Agametic reproduction by fission is a novel trajectory evolved numerous times among animal phyla, including Annelida, in which it is thought to arise by co-option of regeneration. To gain insight into how a novel trajectory may evolve, we investigated a relatively recent origin of fission. We performed a detailed comparison of morphogenesis during regeneration and fission in the annelid Pristina leidyi (Clitellata, Naididae), from the onset of these trajectories to the achievement of the final morphology. We find extensive similarities between fission and regeneration morphogenesis, and, of particular note, find evidence for a synapomorphy of fission and regeneration (apparently not shared with embryogenesis) in peripheral nervous system development, providing strong support for the hypothesis that fission is derived from regeneration. We also find important differences between fission and regeneration, during development of multiple organ systems. These are manifested by temporal shifts in developmental events and by the presence of elements unique to only one process. Differences are not obviously temporally clustered at the beginning, middle, or end of development but rather occur throughout, indicating that divergence has occurred along the entire developmental course of these trajectories.

Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) are the commonest cause of chronic kidney disease in children. Structural anomalies within the CAKUT spectrum include renal agenesis, kidney hypo-/dysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. While most CAKUT cases are sporadic, familial clustering of CAKUT is common, emphasizing a strong genetic contribution to CAKUT origin. Animal experiments demonstrate that alterations in genes crucial for kidney development can cause experimental CAKUT, while expression studies implicate mislocalization and/or aberrant levels of the encoded proteins in human CAKUT. Further insight into the pathogenesis of CAKUT will improve strategies for early diagnosis, follow-up and treatment. Here, we outline a collaborative approach to identify and characterize novel factors underlying human CAKUT. This European consortium will share the largest collection of CAKUT patients available worldwide and undertake multidisciplinary research into molecular and genetic pathogenesis, with extension into translational studies to improve long-term patient outcomes.

Generation of patterned kidney organoids that recapitulate the adult kidney collecting duct system from expandable ureteric bud progenitors.

Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney's collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from human pluripotent stem cells. In chemically-defined culture conditions, UB organoids generate CD organoids, with differentiated principal and intercalated cells adopting spatial assemblies reflective of the adult kidney's collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Applying an efficient gene editing strategy to remove RET activity, we demonstrate genetically modified UB organoids can model congenital anomalies of kidney and urinary tract. Taken together, these platforms will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting duct system.

Roles for urothelium in normal and aberrant urinary tract development.

Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of chronic kidney disease and end-stage kidney disease in children. Increasing evidence points to critical roles for the urothelium in the developing urinary tract and in the genesis of CAKUTs. The involvement of the urothelium in patterning the urinary tract is supported by evidence that CAKUTs can arise as a result of abnormal urothelial development. Emerging evidence indicates that congenital urinary tract obstruction triggers urothelial remodelling that stabilizes the obstructed kidney and limits renal injury. Finally, the diagnostic potential of radiological findings and urinary biomarkers derived from the urothelium of patients with CAKUTs might aid their contribution to clinical care.

[Fetal urology]. / A magzat urológiája.

Although it becomes vitally important only after birth, renal function already plays significant role in maintaining fetal metabolic equilibrium. The kidneys significantly contribute to production of amniotic fluid. Adequate amount of amniotic fluid is needed to stimulate the intrauterine fetal respiratory activity. Intrauterine breathing is essential for lung development. As a result, oligohydramnion is conducive to pulmonary hypoplasia. The latter may lead to neonatal demise soon after birth. In extrauterine life kidneys eliminate nitrogen containing metabolic byproducts. Inadequate renal function results therefore lethal uremia. Integrity of ureters and the urethra is essential for the maintenance of renal function. Retention of urine causes degeneration of the functional units of the kidneys and ensuing deterioration of renal function. Intrauterine kidney puncture or shunt procedure may delay this process in some cases. On the other hand, once renal function has been damaged, no therapy can restart it. Certain anomalies of renal excretory pathways may also be associated with other congenital abnormalities, making the therapeutic efforts pointless. Presence of these associated intrauterine defects makes early pregnancy termination a management alternative, as well as it affects favorably perinatal mortality rates.

Prenatal and postnatal urinary tract dilation: advantages of a standardized ultrasound definition and classification.

Urinary tract dilatation is identified sonographically in 1-2% of fetuses and reflects a spectrum of possible nephro-uropathies. There is significant variability in the clinical management of individuals with prenatal urinary tract dilatation to postnatal urinary pathologies, because of a lack of consensus and uniformity in defining and classifying urinary tract dilation. Ultrasonography is the first step to screen and diagnose kidneys and the urinary tract diseases of the children. The need for a correct ultrasound approach led to the realization of algorithms aimed at standardizing the procedures, the parameters and the classifications. Our objective was to highlight the strengths of the Classification of Urinary Tract Dilation (UTD) suggested by the Consensus Conference which took place in 2014 with the participation of eight Scientific Societies and was subsequently published on the Journal of Pediatric Urology. Before its spread out, the definition of UTD was not uniform and the ultrasonographic measurements were not clearly defined, leading to misunderstandings between physicians. The Classification by the Consensus Conference of 2014 represents a revolutionary tool for the diagnosis and management of UTD. Furthermore, the parameters suggested by the classification proposed are applicable for both prenatal and postnatal classification, ensuring a correct follow-up in children with UTD whose diagnosis had been already made during pregnancy.

Downregulation of Spry-1, an inhibitor of GDNF/Ret, causes angiotensin II-induced ureteric bud branching.

Mutations of genes in the renin-angiotensin system are associated with congenital abnormalities of the kidney and urinary tract. The major signaling pathway for branching morphogenesis during kidney development is the c-Ret receptor tyrosine kinase whose ligand is GDNF and whose downstream target is Wnt11. We determined whether angiotensin II, an inducer of ureteric bud branching in vitro, influences the GDNF/c-Ret/Wnt11 pathway. Mouse metanephroi were grown in the presence or absence of angiotensin II or an angiotensin type 1 receptor (AT1R) antagonist and gene expression was measured by whole mount in situ hybridization. Angiotensin II induced the expression of c-Ret and Wnt11 in ureteric bud tip cells. GDNF, a Wnt11-regulated gene expressed in the mesenchyme, was also upregulated by angiotensin II but this downregulated Spry1, an endogenous inhibitor of Ret tyrosine kinase activity in an AT1R-dependent manner. Angiotensin II also decreased Spry1 mRNA levels in cultured ureteric bud cells. Exogenous angiotensin II preferentially stimulated ureteric bud tip cell proliferation in vivo while AT1R blockade increased cell apoptosis. Our findings suggest AT1R-mediated inhibition of the Spry1 gene increases c-Ret tyrosine kinase activity leading to upregulation of its downstream target Wnt11. Enhanced Wnt11 expression induces GDNF in adjacent mesenchyme causing focal bursts of ureteric bud tip cell proliferation, decreased tip cell apoptosis and branching.

The impact of constipation on the urinary tract system.

The rate of constipation and bowel disorders is underestimated in children and adolescence who suffer from functional urinary tract disorders like enuresis and incontinence. The alimentary and the urinary systems act with a close anatomical and functional relation, malfunctioning of either system will affect the other. Children and adolescents with urinary dysfunctional symptoms have a higher rate of bowel disorders, including constipation and soiling, and vice versa. Assessment and treatment should always include both systems. Failure to detect and treat bowel problems will greatly reduce the success rate in the treatment of urinary symptoms. Dysfunctional symptoms in childhood could be a risk factor for increased rate of constipation and incontinence in adolescence and adulthood. This paper describes the normal development of voiding and defecation control, the effect of bowel disorders on the urinary system, and offers advice concerning the assessment and management of these patients.

ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

[Develooment of the lower urinary tract and its functional disorders].

A normal development of lower urinary tract function control evolves from involuntary bladder empting (incontinence) during infancy to daytime urinary continence, and finally a successful day and night continence that is generally achieved by the 5th to 7th year of age.This gradual process primarily depends on the progressive maturation of the neural control of the lower urinary tract, but it is also influenced by behavioral training that evolves through social support. Functional voiding disorders (bladder dysfunction) are common problems during childhood. They are present in 5-15 % of general pediatric population, and in one-fifth of school-age children or in over one-third of patients of the pediatric urologist or nephrologist. More than half of children with bladder dysfunction have vesicoureteral reflux, and more than two-thirds have recurrent urinary tract infections. There is also a frequent association of bladder dysfunction with constipation and encopresis (dysfunctional elimination syndrome). Bladder dysfunction may cause a permanent damage to the upper urinary tract and kidneys. In addition, urinary incontinence, as the most common manifestation of bladder dysfunction can be the cause of major stress in school- age children and have a negative effect on the child's feeling of self-esteem. Thus, a timely detection and treatment of this group of disorders in children is highly significant.

[Morphofunctional immaturity of the urinary tract and vesicoureteral reflux in young children]. / Morfofunktsional'naia nezrelost' mochevykh putei i puzyrno-mochetochnikovyi refliukc u detei rannego vozrasta.

On the basis of rich clinical experience--593 patients and 916 renoureteral units (RUU) with vesicoureteral reflux (VUR) in infants the authors showed that early recognition of VUR is necessary, which is ensured by adequate organization of service to infants of the "risk group". Complex examination of children by functional diagnostic methods conducted under general anesthesia makes it possible to undertake some methods of examination for the detection and control of morphofunctional immaturity, while early application of purposeful rehabilitation measures in the stages inpatient treatment--outpatient treatment--treatment in the family produces a "positive dynamics" of the course of the pathological process in most patients (up to 82.1%). All this in complex confirms that morphofunctional immaturity of the urinary tract is the main cause of VUR in infants.

Obstructive urolithiasis in growing-finishing pigs / Urolitíase obstrutiva em suínos de crescimento e terminação

Obstructive urolithiasis is a disease characterized by the presence of uroliths in the urinary tract, with consequent obstruction of excretion pathways. This paper described the epidemiological and clinical-pathological findings of 22 outbreaks of urolithiasis in growing-finishing pigs in Southern Brazil. All affected pigs were male and clinical presentation consisted of lethargy, dysuria, rectal prolapse, abdominal distention, peripheral cyanosis and reluctance to move. Clinical progression course ranged from 12 hours to one week, and the lethality rate was 100%. Gross changes were characterized by urinary bladder rupture associated with marked amount of yellowish liquid with ammoniacal odor (urine) in the abdominal cavity (uroperitoneum), as well as mild fibrin deposition on the surface of abdominal organs and hydronephrosis. Urinary uroliths ranging from 0.3 to 1cm in diameter were often observed obstructing the lumen of the penile urethra and sometimes those were free in the abdominal cavity. Histopathological findings included diffuse and marked urinary bladder edema and hemorrhage associated with inflammatory infiltrate of lymphocytes, plasma cells, and macrophages. Diffuse and marked necrosis of the mucosal epithelium was observed in the penile urethra. Intense fibrin deposition and inflammatory infiltrate of neutrophils were noted in the peritoneum, as well as in the serosa of the organs in the abdominal cavity. Uroliths were submitted to the method of qualitative determination of the mineral components, and were compatible with calcium carbonate and magnesium ammonium phosphate. Growing pigs ration analysis revealed low levels of calcium in relation to phosphorus, resulting in a Ca:P ratio of approximately 0.35:1. Histological findings and mineral analysis suggest that outbreaks of urolithiasis were related to a nutritional imbalance in the proportions of dietary calcium and phosphorus. The main cause of mortality was related to dehydration and uroperitoneum.(AU)

Urolitíase obstrutiva é uma enfermidade caracterizada pela presença de urólitos no trato urinário, com consequente obstrução das vias de excreção. Este artigo descreve os achados epidemiológicos e clínico-patológicos de 22 surtos de urolitíase em suínos de crescimento e terminação no Sul do Brasil. Os suínos afetados eram machos e clinicamente apresentavam letargia, disúria, prolapso retal, abaulamento do abdômen, extremidades cianóticas e relutância em movimentar-se. A duração dos sinais clínicos variou de 12 horas a uma semana, e a letalidade foi de 100%. As alterações macroscópicas caracterizaram-se por ruptura da bexiga com acentuada quantidade de líquido de coloração amarelada e odor amoniacal (urina) livre na cavidade abdominal (uroperitônio), além de discreta deposição de fibrina sobre os órgãos e hidronefrose. Frequentemente obstruindo o lúmen da uretra peniana e por vezes livre na cavidade abdominal, era possível observar urólitos urinários que variavam de 0,3 a 1cm de diâmetro. Os achados histopatológicos incluíram edema e hemorragia difusos e acentuados na bexiga, associado a infiltrado inflamatório predominante de linfócitos, plasmócitos e macrófagos. Na uretra peniana havia necrose difusa e acentuada do epitélio da mucosa. No peritônio e nas serosas dos órgãos da cavidade abdominal havia intensa deposição de fibrina e infiltrado neutrofílico. Os urólitos foram submetidos ao método de determinação qualitativa dos componentes minerais, os quais foram compatíveis com carbonato de cálcio e fosfato de amônio magnesiano. A análise da ração de crescimento revelou baixos níveis de cálcio, em relação ao fósforo, perfazendo uma relação Ca:P de aproximadamente 0,35:1. Os achados histológicos e as dosagens minerais sugerem que os surtos de urolitíase foram relacionados a um desequilíbrio nutricional nas proporções de cálcio e fósforo dietético. A principal causa da morte dos suínos foi relacionada à desidratação e ao uroperitônio.(AU)

Development of the urinary system in guinea pig females (Cavia porcellus) / Desenvolvimento do sistema urinário em fêmeas de porquinhos-da-índia (Cavia porcellus)

Guinea pigs are animal models widely used in research related to developmental biology. The objective of this work was to demonstrate the process of formation and differentiation of urinary organs in females of the species in the prenatal period. Four females were used at 25, 30, 45 and >65 DG (days of gestation). The animals were dissected, and then macroscopic and microscopic descriptions of the urinary organs were performed. At 25 DG metanephros were present in the urogenital crest into the abdominal cavity. Collecting ducts and glomerular precursor cells could be visualized. After this period, metanephros underwent microstructural modifications to form the kidneys at the end of the prenatal period. After 30 DG, the renal parenchyma already had a cortex, where the glomerulus and proximal convoluted tubules were present; and the medulla, where distal convoluted tubules, collecting ducts, and pelvis were present. The pelvis of each kidney was drained by the ureters. The ureters also underwent tissue differentiation to be differentiated (mucosa with transitional epithelium and lamina propria of connective tissue, muscular, and adventitia) at the end of the prenatal period. The urinary vesicle also underwent tissue changes to form the tunics similar to those found in the ureters, with emphasis on the greater volume of the muscular tunica and the lamina propria that constituted the submucosa in this organ. The pelvic urethra was evidenced by a mucosa lined by transitional epithelium, submucosa, muscular and adventitia. Finally, a partial clitoral urethra and a urethral meatus in the prepuce of the clitoris were also evidenced. The urethral channel began to form with the emergence of the urethral plate and the urethral groove at 30 DG and thereafter with the fusion of the urethral folds to form a partially channeled urethra in the clitoris. A urethral meatus was observed in the most distal portion of the clitoral tissue, formed by the fusion of the prepuce. It is concluded that the urinary organs of guinea pig have similar development to that described in domestic animals, except for the partial clitoral urethra and evident urethral meatus.(AU)

Os porquinhos-da-índia são modelos animais amplamente utilizados em pesquisas relacionadas a biologia do desenvolvimento. O objetivo deste trabalho foi demonstrar o processo de formação e diferenciação dos órgãos urinários em fêmeas da espécie no período pré-natal. Foram utilizadas quatro fêmeas aos 25, 30, 45 e >65 DG (dias de gestação). Os animais foram dissecados e então, realizaram-se descrições macroscópicas e microscópicas dos órgãos urinários. Aos 25 DG os metanefros estavam presentes na crista urogenital da cavidade abdominal. Podiam ser visualizados ductos coletores e células precursoras glomerulares. Após este período, os metanefros sofreram modificações microestruturais para formar os rins ao final do período pré-natal. Após os 30 DG, o parênquima renal já apresentava um córtex, onde estavam presentes os glomérulos e túbulos convolutos proximais, e a medula onde estavam presentes túbulos convolutos distais, ductos coletores e a pelve. A pelve de cada rim era drenada pelos ureteres. Os ureteres também sofreram diferenciação tecidual para estarem com suas túnicas diferenciadas (mucosa com epitélio de transição e lâmina própria de tecido conjuntivo; muscular; e, adventícia) ao final do período pré-natal. A vesícula urinária também passou por modificações teciduais para formar as túnicas semelhantes as dos ureteres, com destaque para o maior volume da túnica muscular e a lâmina própria que constituiu a submucosa neste órgão. Uma uretra pélvica foi evidenciada por uma mucosa revestida por epitélio de transição, submucosa, muscular e adventícia. Por último, uma uretra parcialmente clitoriana e um meato uretral no prepúcio do clitóris também foi evidenciado. O canal uretral começou a se formar com o aparecimento da placa uretral e do sulco uretral aos 30 DG e posteriormente com a fusão das pregas uretrais para formar uma uretra parcialmente canalizada no clitóris. Observou-se um meato uretral na porção mais distal do tecido clitoriano, formado pela fusão do prepúcio. Conclui-se que os órgãos urinários do porquinho-da-índia possuem desenvolvimento semelhante ao descrito em animais domésticos, com exceção da uretra parcialmente clitoriana e do meato uretral evidente.(AU)

Retinoid signaling in progenitors controls specification and regeneration of the urothelium.

The urothelium is a multilayered epithelium that serves as a barrier between the urinary tract and blood, preventing the exchange of water and toxic substances. It consists of superficial cells specialized for synthesis and transport of uroplakins that assemble into a tough apical plaque, one or more layers of intermediate cells, and keratin 5-expressing basal cells (K5-BCs), which are considered to be progenitors in the urothelium and other specialized epithelia. Fate mapping, however, reveals that intermediate cells rather than K5-BCs are progenitors in the adult regenerating urothelium, that P cells, a transient population, are progenitors in the embryo, and that retinoids are critical in P cells and intermediate cells, respectively, for their specification during development and regeneration. These observations have important implications for tissue engineering and repair and, ultimately, may lead to treatments that prevent loss of the urothelial barrier, a major cause of voiding dysfunction and bladder pain syndrome.

Lower urinary tract development and disease.

Congenital anomalies of the lower urinary tract (CALUT) are a family of birth defects of the ureter, the bladder, and the urethra. CALUT includes ureteral anomaliesc such as congenital abnormalities of the ureteropelvic junction (UPJ) and ureterovesical junction (UVJ), and birth defects of the bladder and the urethra such as bladder-exstrophy-epispadias complex (BEEC), prune belly syndrome (PBS), and posterior urethral valves (PUVs). CALUT is one of the most common birth defects and is often associated with antenatal hydronephrosis, vesicoureteral reflux (VUR), urinary tract obstruction, urinary tract infections (UTI), chronic kidney disease, and renal failure in children. Here, we discuss the current genetic and molecular knowledge about lower urinary tract development and genetic basis of CALUT in both human and mouse models. We provide an overview of the developmental processes leading to the formation of the ureter, the bladder, and the urethra, and different genes and signaling pathways controlling these developmental processes. Human genetic disorders that affect the ureter, the bladder and the urethra and associated gene mutations are also presented. As we are entering the postgenomic era of personalized medicine, information in this article may provide useful interpretation for the genetic and genomic test results collected from patients with lower urinary tract birth defects. With evidence-based interpretations, clinicians may provide more effective personalized therapies to patients and genetic counseling for their families.