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      Polymorphic Genes for Kinin Receptors, Nephropathy and Blood Pressure in Type 2 Diabetic Patients

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          Background/Aims: There is evidence that hereditary predisposition contributes to the development of diabetic nephropathy and hypertension. Polymorphisms in the genes for bradykinin receptors (B<sub>1</sub>R and B<sub>2</sub>R) were found to be associated with decreased risk of the development of end-stage renal disease. This study examines whether B<sub>1</sub>R G<sup>–699</sup>C and B<sub>2</sub>R C<sup>181</sup>T polymorphisms are associated with microalbuminuria or overt nephropathy, or blood pressure variation in type 2 diabetic subjects. Methods: B<sub>1</sub>R and B<sub>2</sub>R polymorphisms were determined in 153 type 2 diabetic patients with microalbuminuria, 132 with overt nephropathy (macroalbuminuria or chronic renal failure), and 161 patients with normoalbuminuria despite diabetes duration longer than 10 years. Results: Distributions of the examined polymorphisms did not differ between patients with microalbuminuria or overt nephropathy, compared to normoalbuminuric control subjects. Patients carrying the B<sub>2</sub>R T allele had lower DBP, compared with non-carriers: 83.6 ± 12.0 vs. 87.4 ± 12.1 mm Hg, p < 0.05. Among patients not receiving ACEI, both SBP and DBP was significantly lower in B<sub>2</sub>R T allele carriers, compared to non-carriers (137.2 ± 20.3 vs. 146.5 ± 21.7 mm Hg, and 80.3 ± 11.9 vs. 85.8 ± 11.6 mm Hg, p < 0.05). Conclusions: Examined polymorphisms are not associated with the increased risk of incipient or overt nephropathy in type 2 diabetic patients. B<sub>2</sub>R C<sup>181</sup>T polymorphism may contribute to blood pressure variation in these subjects.

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          Most cited references 7

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          Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects.

          Angiotensin-converting-enzyme (ACE) inhibitors not only decrease the production of angiotensin II but also decrease the degradation of bradykinin. In this study, a specific bradykinin-receptor antagonist, icatibant acetate (HOE 140), was used to determine the contribution of bradykinin to the short-term effects of ACE inhibition on blood pressure and plasma renin activity in both normotensive and hypertensive subjects. We compared the hemodynamic, renal, and endocrine effects of captopril alone (25 mg), captopril plus icatibant (100 microg per kilogram of body weight), the angiotensin II subtype 1-receptor antagonist losartan (75 mg), and placebo in 20 subjects with normal blood pressure and 7 subjects with hypertension. The subjects were studied while they were salt depleted (i.e., in balance on a diet in which they were allowed 10 mmol of sodium per day). The drugs were administered on four separate study days in a single-blind, randomized fashion. The coadministration of icatibant significantly attenuated the hypotensive effect of captopril (maximal decrease in mean arterial pressure for all subjects combined, 10.5+/-1.0 mm Hg, as compared with 14.0+/-1.0 mm Hg for captopril alone; P=0.001), in such a way that the decrease in blood pressure after the administration of captopril plus icatibant was similar to that after the administration of losartan (maximal decrease in mean arterial pressure, 11.0+/-1.7 mm Hg). Icatibant did not alter the renal hemodynamic response to captopril, but it significantly altered the change in plasma renin activity in response to ACE inhibition (-0.4+/-0.4 ng of angiotensin I per milliliter per hour, as compared with 2.0+/-0.7 ng per milliliter per hour for captopril alone; P=0.007). The magnitude of these effects was similar in both the normotensive and the hypertensive subjects, as well as in both the black subjects and the white subjects. These data confirm that bradykinin contributes to the short-term effects of ACE inhibition on blood pressure in normotensive and hypertensive persons and suggest that bradykinin also contributes to the short-term effects of ACE inhibition on the renin-angiotensin system.
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            Altered frequency of a promoter polymorphism of the kinin B2 receptor gene in hypertensive African-Americans.

            Components of the kallikrein kinin system have been associated with the pathophysiology of hypertension in animal and human studies. In this study, we examined the distribution of four different polymorphisms of the kinin B1 and B2 receptor genes in a population of 120 normotensive and 77 hypertensive African-Americans. Allelic frequencies for three of the four polymorphisms were significantly different from those previously reported in Caucasian populations. Among the polymorphisms analyzed, a potentially functionally significant polymorphism in the core promoter of the kinin B2 receptor (C-58-->T transition) displayed an increased prevalence of the C-58 allele in the hypertensive patients as compared with the controls (0.75 v. 0.62, P = .009). Thus, this B2 receptor promoter polymorphism may represent a susceptibility marker for essential hypertension in African-Americans.
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              A novel sequence polymorphism in the promoter region of the human B2-bradykinin receptor gene.

              The distribution of a nucleotide polymorphism in the core promoter of the human B2-bradykinin receptor gene was examined in the population of southern Germany. The allelic frequencies were 0.595 for C allele and 0.405 for the T allele. The allele frequencies were in Hardy-Weinberg equilibrium. This new marker provides a valuable tool to assess the risk for putative bradykinin-associated disorders with genetic determinism.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                April 2003
                17 January 2003
                : 23
                : 2
                : 112-116
                Department of Internal Medicine, Diabetology and Nephrology, Silesian School of Medicine, Zabrze, Poland
                68035 Am J Nephrol 2003;23:112–116
                © 2003 S. Karger AG, Basel

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                Page count
                Tables: 2, References: 35, Pages: 5
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                Original Article: Patient-Oriented, Translational Research


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