Angiotensin type 2 receptor is important in the normal development of the ureter

Hohenfellner, Katharina; Hunley, Tracy E.; Schloemer, Carde; Brenner, Walburgis; Yerkes, Elizabeth B.; Zepp, Fred; Brock, John W.; Kon, Valentina

doi:10.1007/s004670050589

Cited by 49 publications

(36 citation statements)

References 26 publications

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“…A lower frequency of G allele in males with ureteral obstruction was found in our population. On the contrary, previous studies showed a significantly higher frequency in Caucasian males with UPJO or UVJO (7,9), whereas another study in Japanese males showed no difference (10). The discrepancy among these studies is more likely to be the result of the limited number of included patients because the genetic background, at least among Caucasians, does not differ.…”

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confidence: 46%

“…In contrast, Yim et al (17) found that this transition occurred significantly less often in Korean patients (males and females) with VUR than in normal controls. Previous studies (9,11), including ours, showed no significant difference in the frequency of the A-G transition in patients with PUV, which is expected because the At2r mRNA expression is absent in the urethral area (7).…”

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confidence: 58%

“…AT2R GENE AND CONGENITAL UROPATHIES population (57%) compared with other Caucasian (38%-42%) (7,9,16,18) and Japanese (30%) (10) controls. In Table 5, previous studies considering the A-1332G transition in patients with CAKUT are summarized.…”

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confidence: 99%

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Angiotensin II Type 2 Receptor Gene Polymorphism in Caucasian Children With a Wide Spectrum of Congenital Anomalies of the Kidney and Urinary Tract

et al. 2007

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ABSTRACT:The A-1332G transition of the angiotensin II type 2 receptor (AT2R) gene was found to occur more often in males with ureteropelvic (UPJO) or ureterovesical junction obstruction (UVJO). However, other studies have shown controversial results. ⌻he frequency of this polymorphism was investigated in 275 Caucasian children (153 boys, 122 girls) with a wide spectrum of congenital anomalies both of upper (165) and lower (110) urinary tract system and in 200 controls (100 boys, 100 girls). Among the included malformations, renal agenesis and duplex collecting system (DCS) were studied for the first time. The frequency of the G allele did not differ among patients (193 of 397 total alleles, 48.6%) and controls (146 of 300, 48.7%). No significant difference was also found in the frequency of the G allele in subgroups of congenital uropathies compared with controls. When analysis was performed in males and females separately, no significant difference was found in the frequency of the G allele in male (45.1%) or female (50.8%) patients compared with male (57.0%) or female (44.5%) controls. Our data indicate that the AT2R gene A-1332G transition is not associated with the development of human congenital uropathies and further investigations should be carried out to unravel their etiology. C ongenital anomalies of the kidney and urinary tract (CAKUT) account for up to 30% of all anomalies diagnosed prenatally and constitute the main cause of chronic renal failure in infants and young children. Although the etiology of most of these anomalies has not been identified, experimental studies have identified several genes that are implicated in nephrogenesis and in which the derangement result in renal maldevelopment (1,2).In recent years, published data have shown that the reninangiotensin system, besides its role in maintaining blood pressure as well as fluid and electrolytes homeostasis, has an important role in kidney development (3). AT2R is abundantly expressed in fetal tissues (4) and decreases rapidly after birth (5). It has been shown to mediate programmed cell death, playing an important role in developmental biology and pathophysiology (4). The expression of the AT2R is higher and localized to the mesenchyme at the time of the ureteric bud branching (3). The gene encoding AT2R is located on the X chromosome, so that normal males carry only one copy, whereas normal females carry two copies. It consists of three exons and two introns, with the entire coding region located on exon 3 (6).Experimental studies have shown that the establishment of CAKUT is preceded by delayed apoptosis of the undifferentiated mesenchymal cells that initially occupy the metanephros and densely surround the wolffian duct and ureter (7). This abnormal apoptosis hinders the normal interaction between the ureteric bud and metanephric blastema, resulting in CAKUT (8). Moreover, At2r gene null mutant mice display CAKUT, which mimics human CAKUT (7).Studies on the human AT2R gene identified a polymorphic locus in a large proportion of the gen...

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Angiotensin II Type 2 Receptor Gene Polymorphism in Caucasian Children With a Wide Spectrum of Congenital Anomalies of the Kidney and Urinary Tract

et al. 2007

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“…Available data support two mechanistic scenarios on how ectopic c-Ret/GFR␣1 activation might occur: (1) Anterior expansion of the GDNF field (i.e., anterior to the specified metanephric anlagen) as a result of loss of a GDNF repressor, such as Foxc1 or Slit2/Robo2 13,14 ; and (2) increased responsiveness of the duct to GDNF from loss of antagonistic signals, such as Sprouty1 in the WD, 15 or around the duct in the periureteral mesenchyme, such as Bmp4 or Agtr2. 16,17 Both models are accompanied by ectopic GDNFRet activity. Thus, there is clear evidence of control at multiple levels to ensure normal metanephric development.…”

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p53 Regulates Metanephric Development

Saifudeen

Dipp

Stefkova

et al. 2009

Journal of the American Society of Nephrology

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p53 is best known as a tumor suppressor that regulates cell-cycle, differentiation, and apoptosis pathways, but its potential role in embryonic development and organogenesis remains controversial. Here, p53Ϫ/Ϫ embryos bred on C57Bl6 background exhibited a spectrum of congenital abnormalities of the kidney and urinary tract, including ureteric bud (UB) ectopia, double ureters/collecting systems, delayed primary branching of the UB, and hypoplastic metanephroi. We observed ectopic UB outgrowth from the Wolffian duct (WD) in one third of p53 Ϫ/Ϫ embryos. The prevalence of duplex was higher in embryos than in neonates, and ex vivo organ culture suggested that ectopic ureters can regress over time, leaving behind a dysplastic pole ("segmental dysgenesis"). Transgenic expression of dominant negative p53 or conditional inactivation of p53 in the UB but not in the metanephric mesenchyme lineage recapitulated the duplex phenotype. Mechanistically, p53 inactivation in the WD associated with enhanced sensitivity to glial cell line-derived neurotrophic factor (GDNF)-induced ectopic budding and potentiated phosphatidylinositol-3 kinase activation by GDNF in UB cells. Unlike several other models of UB ectopia, hypersensitivity of p53 Ϫ/Ϫ WD to GDNF is not accompanied by reduced Sprouty-1 or anterior expansion of the GDNF domain. In summary, our data lend support for a restrictive role for p53 activity in UB outgrowth from the WD. Organogenesis is dependent on a multitude of growth factors, signaling molecules, and transcription factors that temporally and spatially define a developmental program. Metanephric development is dependent on formation of the Wolffian duct (WD) and the adjacent metanephric mesenchyme (MM) from the intermediate mesoderm. In mice, the ureteric bud (UB) develops at embryonic day 10.5 (E10.5) from the caudal end of the WD. Inductive interactions between the UB and the MM ensure cell survival and subsequent onset of metanephrogenesis. Emergence of the UB from a specific site in the WD adjacent to the MM is controlled by the glial cell line-derived neurotrophic factor (GDNF)-cRet signaling pathway. 1-6 GDNF is a growth factor that is secreted by the MM and binds to its receptor c-Ret and co-receptor GFR␣1 that are expressed along the WD and UB tips. Stimulation of the GDNF-cRet pathway results in cell proliferation and chemotaxis. 7,8 After the initial broad distribution of the GDNF field along the posterior half of the WD, the GDNF expression domain is progressively restricted to the caudal end of the WD in the immediate vicinity of the site of UB outgrowth 9 -11 ; however, the potential for bud emergence remains along the length of the WD, which continues to express the c-Ret/GFR␣1 receptor/co-receptor. Evidence from mutant mouse models and metanephric organ culture implicates impaired restriction of the GDNF field and the GDNF/c-Ret signaling pathway in ureter duplica-

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“…An example is provided by the association of a polymorphism, or common genetic variation, of the angiotensin II type 2 receptor (AT2) gene with a spectrum of disorders including pelviureteric junction obstruction and megaureter (13,16). The genetic variant most likely affects splicing and mRNA transcript levels of this growth factor receptor implicated in cell survival in developing kidney and lower urinary tract (13).…”

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confidence: 99%

The Life of the Human Kidney Before Birth: Its Secrets Unfold

Woolf

2001

Pediatr Res

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Angiotensin type 2 receptor is important in the normal development of the ureter

Cited by 49 publications

References 26 publications

Angiotensin II Type 2 Receptor Gene Polymorphism in Caucasian Children With a Wide Spectrum of Congenital Anomalies of the Kidney and Urinary Tract

Angiotensin II Type 2 Receptor Gene Polymorphism in Caucasian Children With a Wide Spectrum of Congenital Anomalies of the Kidney and Urinary Tract

p53 Regulates Metanephric Development

The Life of the Human Kidney Before Birth: Its Secrets Unfold

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