ACE and AT1 receptor gene polymorphisms and renal scarring in urinary bladder dysfunction

Abstract

The objective of this study was to investigate whether DNA polymorphisms of the renin-angiotensin system (RAS) genes were associated with renal scar formation in pediatric patients with bladder dysfunction (BD). Although these children are born healthy, due to persistence of immature voiding habits and evolution of BD, some develop progressive renal damage. It has been suggested that the DD genotype of the angiotensin I-converting enzyme (ACE) gene might be an adverse renal prognostic factor. The insertion/deletion (I/D) polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor (ATR1) gene were identified by polymerase chain reaction amplification in 42 children with BD (aged 5-14 years) and 198 healthy adult controls. Twelve children had urgency syndrome and 30 had dysfunctional voiding. Renal scarring was found in 16 patients, while 26 patients had normal kidneys on dimercaptosuccinic acid scan. In children with renal lesions there was significant over-representation of the DD genotype compared with either controls or patients without renal damage ( P<0.05). On multivariate analysis, the DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 2.51-fold risk (odds ratio 2.51, 95% confidence interval 1.04-6.04, P=0.04). The A1166C gene polymorphism was not significantly associated with the development of parenchymal damage in children with BD. Our findings introduce ACE I/D gene polymorphism as an independent risk factor for parenchymal destruction in pediatric patients with BD.

Polymorphisms of the angiotensin converting enzyme and angiotensin II type 1 receptor genes and renal scarring in non‐uropathic children with recurrent urinary tract infection

“…Like in many other disease states, genetic polymorphism might be a predisposing factor. However, almost all of the studies investigating the role of RAS gene polymorphisms on renal scar formation related to UTI have been performed in patients with urological abnormality 5,6 , 13,17 , 18 …”

“…However, almost all of the studies investigating the role of RAS gene polymorphisms on renal scar formation related to UTI have been performed in patients with urological abnormality. 5,6,13,17,18 Studies investigating the relationship between ACE DD genotype and scar formation in patients with VUR has given contradictory results. Some studies found an association between the ACE DD genotype and renal scar development in patients with VUR, 5,13,18,22 but other studies did not support this association.…”

“…In some previous studies, an association between the I/D of the ACE genotype and scar formation in different nephropathies (i.e. IgA nephropathy, VUR nephropathy, diabetic nephropathy, focal segmental glomerulosclerosis, autosomal dominant polycystic disease and bladder dysfunction) has been reported 5,9–13 . However, subsequent studies have provided contradictory results.…”

“…IgA nephropathy, VUR nephropathy, diabetic nephropathy, focal segmental glomerulosclerosis, autosomal dominant polycystic disease and bladder dysfunction) has been reported. 5,[9][10][11][12][13] However, subsequent studies have provided contradictory results. For example, the Diabetic Nephrology Study Group showed no correlation between the ACE genotype and progression to nephropathy.…”

ACE gene insertion/deletion polymorphism and renal scarring in children with urinary tract infections

“…Mizuiri et al [6] reported that the I/D polymorphism affects renal tissue ACE levels and that DD subjects have pronounced renal ACE gene expression. Theoretically, elevated ACE leads to elevated angiotensin II, which promotes proliferation, inflammation, and fibrosis, the main features of renal scarring [18]. Angiotensin II binds to its receptors, AT1 and AT2, and, through the activation of different intracellular signaling pathways, mediates the production of various profibrotic and proinflammatory factors, such as transforming growth factors, cytokines, chemokines, and adhesion molecules [19].…”