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

Abstract

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...

Association of angiotensin type 2 receptor gene polymorphisms with ureteropelvic junction obstruction in Brazilian patients

“…reported that there is no evidence for this AGTR2 gene derangement in human urinary tract anomalies in Japanese patients. The frequency of the G allele in the AGTR2 gene was higher in CAKUT patients than in the general population in Italian and Korean children, while no differences were found in a more recent study from Greece . Nishimura's subjects were selected through strict inclusion criteria, namely male UPJO/MCDK patients .…”

“…Nishimura's subjects were selected through strict inclusion criteria, namely male UPJO/MCDK patients . In contrast, the Japanese, the Italian, the Korean and the Greek CAKUT samples included male and female patients with various phenotypes. The Korean study reported that the A–G transition in intron 1 of the AGTR2 gene is associated with UPJO/MCDK, whereas, in the Greek study, the same transition of the AGTR2 gene was not associated with the development of the CAKUT .…”

“…It has been reported that A to G transition at the 1332 position in AGTR2 gene is associated with abnormal splicing, producing shorter length mRNA and thereby affecting AT 2 receptor activity . This polymorphism has been inconsistently shown to be associated with CAKUT in Caucasians, Korean and Japanese subjects …”

Association of angiotensin converting enzyme and angiotensin type 2 receptor gene polymorphisms with renal damage in posterior urethral valves

“…Recently, Hahn et al also showed a significantly higher frequency of the G allele in Korean patients with urological anomalies compared to the general population [26]. A lack of association of the AT2R A1332G polymorphism with CAKUT has been reported by some workers but they had grouped heterogeneous types of anomaly together [13,27].…”

Angiotensin II type 2 receptor gene polymorphisms in cardiovascular disease

“…It should be noted that this association with CAKUT has not been confirmed in later studies. 10,11 Sequence analysis revealed that the polymorphism was within the only 7-nucleotide sequence that conforms to the consensus for the DNA sequence and physical location required to function as a lariat branchpoint in intron 1, important for mRNA processing. This raised the question as to whether this polymorphism might alter the AT 2 receptor mRNA splice pattern and hence downstream expression levels of functional AT 2 receptors.…”