Each year, more than 40,000 new patients require treatment for end stage renal disease, a condition which is 4-fold higher among African Americans than Caucasians. Trials of angiotensin converting enzyme inhibitors (ACEIs) in Caucasians support a role of the renin-angiotensin system in the pathogenesis of glomeruloscerlosis. Yet, despite the high prevalence of nephropathy among African Americans, blacks have been under-represented in studies in ACEIs. Data from our laboratory suggest that the renal effects of ACEI may differ in African Americans. African Americans are resistant to the anti-hypertensive effects of ACEI and, thus, may be resistant to the renoprotective effects as well. The ACE deletion allele, a variant associated with increased ACE activity and progression of renal diseases, is increased in frequency in African Americans, while the frequency of the Ang AT1 receptor C allele, a variant associated with antihypertensive responsiveness to ACEI is decreased. Moreover, African Americans exhibit decreased sensitivity to Ang I and increased sensitivity to bradykinin. Taken together, these data suggest the hypothesis that ACE activity is increased in African Americans, leading to decreased bradykinin levels (and receptor sensitization) and increased tissue Ang II (and receptor desensitization). To test this hypothesis, we will determine the effect of race, hypertension and ACE insertion/deletion genotype on ACE activity, as measured by the pressor and renal vasoconstrictor responses to Ang I and Ang II (SPECIFIC AIM 1) and the vasodilator response to bradykinin (SPECIFIC AIM 2).
In SPECIFIC AIM 3, we will use specific bradykinin and angiotensin receptor antagonists to determine the relative contribution of increased bradykinin and decreased angiotensin II to the renal hemodynamic effects of ACEIs in African Americans and Caucasians. These studies will provide an understanding of the mechanisms underlying racial differences in progression of renal disease and response to ACEI therapy.
| Gainer, J V; Brown, N J; Bachvarova, M et al. (2000) Altered frequency of a promoter polymorphism of the kinin B2 receptor gene in hypertensive African-Americans. Am J Hypertens 13:1268-73 |
| Brown, N J; Blais Jr, C; Gandhi, S K et al. (1998) ACE insertion/deletion genotype affects bradykinin metabolism. J Cardiovasc Pharmacol 32:373-7 |
| Brown, N J; Vaughan, D E (1998) Angiotensin-converting enzyme inhibitors. Circulation 97:1411-20 |
