The influence of the ACE (I/D) polymorphism on systemic and renal vascular responses to angiotensins in normotensive, normoalbuminuric Type 1 diabetes mellitus
Abstract:Aim/hypothesis. The renin-angiotensin-aldosterone system is important in diabetic nephropathy, with the angiotensin-converting-enzyme DD-genotype being a renal risk factor. The D-allele is associated with higher ACE concentrations, but functional consequences in diabetes mellitus are not known. To analyse these consequences, we assessed renal and systemic responsiveness to angiotensin I infusion, with the response to angiotensin II as reference. Methods. Uncomplicated Type 1 (insulin-dependent) diabetic patien… Show more
“…This is consistent with previous findings concerning kidney function and blood pressure in type 1 diabetic subjects selected on the basis of ACE genotype, studied during hyperglycemia (31), and during infusions of angiotensins 1 and 2 (32). During normoglycemia, ramipril had a dose-dependent effect on renal hemodynamics that did not differ with genotype.…”
Section: Discussionsupporting
confidence: 92%
“…There is evidence to suggest that the reninangiotensin system is highly active during hyperglycemia in the renal circulation of subjects with type 1 diabetes (34,35). We and others (14,31,32) have demonstrated that these renal hemodynamic changes are greater in subjects carrying the ACE D allele than in those with the II genotype. Intraglomerular capillary hydraulic pressure, the main determinant of renal failure (36), is largely conditioned by interaction between the vasodilatory effects of nitric oxide (NO) and the vasoconstrictive effects of angiotensin 2.…”
Section: Discussionmentioning
confidence: 65%
“…This phenomenon may account for the impact of the ACE D allele on renal circulation in type 1 diabetes (14,31,32). The well-known endothelial dysfunction observed in people with diabetes is primarily explained by a low capacity for NO-dependent vasodilatation (38), as a direct consequence of hyperglycemia (39).…”
ACE inhibition protects kidney function, but ACE insertion/ deletion (I/Dassociated with nephroprotection) versus 22 age-and sex-matched subjects with the ACE D allele after three randomly allocated 2-to 6-week periods on placebo, 1.25 mg/day ramipril, and 5 mg/day ramipril in a double-blind, cross-over study. During normoglycemia, the hemodynamic changes induced by ramipril were similar in both genotypes. During hyperglycemia, the changes induced by ramipril were accentuated in the II genotype group and attenuated dose dependently in the D allele group (treatment-genotype interaction P values for ERPF, 0.018; MAP, 0.018; and total renal resistances, 0.055). These results provide a basis to different renal responses to ACE inhibition according to ACE genotype in type 1 diabetes.Diabetes
“…This is consistent with previous findings concerning kidney function and blood pressure in type 1 diabetic subjects selected on the basis of ACE genotype, studied during hyperglycemia (31), and during infusions of angiotensins 1 and 2 (32). During normoglycemia, ramipril had a dose-dependent effect on renal hemodynamics that did not differ with genotype.…”
Section: Discussionsupporting
confidence: 92%
“…There is evidence to suggest that the reninangiotensin system is highly active during hyperglycemia in the renal circulation of subjects with type 1 diabetes (34,35). We and others (14,31,32) have demonstrated that these renal hemodynamic changes are greater in subjects carrying the ACE D allele than in those with the II genotype. Intraglomerular capillary hydraulic pressure, the main determinant of renal failure (36), is largely conditioned by interaction between the vasodilatory effects of nitric oxide (NO) and the vasoconstrictive effects of angiotensin 2.…”
Section: Discussionmentioning
confidence: 65%
“…This phenomenon may account for the impact of the ACE D allele on renal circulation in type 1 diabetes (14,31,32). The well-known endothelial dysfunction observed in people with diabetes is primarily explained by a low capacity for NO-dependent vasodilatation (38), as a direct consequence of hyperglycemia (39).…”
ACE inhibition protects kidney function, but ACE insertion/ deletion (I/Dassociated with nephroprotection) versus 22 age-and sex-matched subjects with the ACE D allele after three randomly allocated 2-to 6-week periods on placebo, 1.25 mg/day ramipril, and 5 mg/day ramipril in a double-blind, cross-over study. During normoglycemia, the hemodynamic changes induced by ramipril were similar in both genotypes. During hyperglycemia, the changes induced by ramipril were accentuated in the II genotype group and attenuated dose dependently in the D allele group (treatment-genotype interaction P values for ERPF, 0.018; MAP, 0.018; and total renal resistances, 0.055). These results provide a basis to different renal responses to ACE inhibition according to ACE genotype in type 1 diabetes.Diabetes
“…20,21 These findings strongly suggest that the enhanced progression of kidney function loss in DD and ID patients is the result of increased intrarenal activity of ACE. 5 In addition, the ACE/DD genotype has been shown to enhance the risk of developing diabetic glomerulopathy lesions in type 2 diabetic patients with microalbuminuria and macroalbuminuria. 22 In addition to nongenetic factors, drug responses are also known to be influenced by inherited factors (i.e., pharmacogenomics).…”
Section: Discussionmentioning
confidence: 99%
“…5 A meta-analysis of 14,727 type 1 and type 2 diabetic patients revealed an enhanced risk for development of diabetic nephropathy in the DD genotype compared with the II genotype. 6 Originally, Parving et al observed that the deletion allele of the ACE polymorphism reduces the long-term beneficial effect of ACE inhibition on the progression of overt diabetic nephropathy in patients with type 1 diabetes.…”
Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment ϫ genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P ϭ 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5. 8% (95% confidence interval, Ϫ23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.