The deletion genotype of ACE (I/D) polymorphism is a risk factor for progressive renal function loss in non-diabetic and diabetic renal disease. The mechanism of the increased renal risk is poorly understood. ACE activity is elevated in the DD genotype, suggesting that alterations in the renin-angiotensin-aldosterone system (RAAS) may play a role. This assumption is supported by increased responses of blood pressure (BP), GFR and aldosterone to exogenous Ang I in healthy DD homozygotes. These enhanced angl responses are normalized by sodium restriction.
lnteraction between ACE genotype and sodium status was also found for therapy response. This suggests that background endogenous RAAS activity may be a determinant of the impact of the D-allele. Several studies suggest involvement of tissue (rather than circulating) RAAS activity. Taken together, the evidence suggests that ACE genotype is associated with alterations in the RAAS that bear impact on regulation of BP and renal function. This physiological constitution as such does not induce renal damage, but appears to set the stage for a poor renal prognosis once other factors initiate renal disease. lnsulin dependent diabetes (IDDM) is a condition where the D- allele increases renal and cardiovascular risk. Moreover, IDDM is associated with alterations in responses to RAAS stimuli well before the onset of target organ damage, such as increased pressor responses to Ang II. To prevent the renal risk associated with the D-allele in WM, elucidation of its mechanisms is crucial. So far, no systematical data on the (patho)physiology of ACE genotype in IDDM are available.
Our aim is to provide such a systematical exploration in uncomplicated IDDM. As both physiology (1) and therapy response (2) may be affected, both wil be studied.
Ad 1: responses of BP, renal hemodynamics and RAAS hormones to Ang l are studied in subjects of different ACE genotype. They are studied on low and liberal sodium to assess whether low sodium can correct possible enhanced responses in DD-genotype.
Ad 2: the effect of genotype on responses of BP and renal hemodynamics to ACE inhibition is studied. Subjects are studied during different sodium intakes and different glycemic states to identify interaction with these environmental factors. The change in renal response to Ang II by ACEi will provide an index of the effect on renal RAAS activity. |
