ACE gene insertion/deletion polymorphism modulates capillary permeability in hypertension

A D/D (deletion/deletion) polymorphism within the ACE (angiotensin 1-converting enzyme) gene increases the risk of microalbuminuria, a predictor of atherosclerotic vascular disease, in essential hypertension. It is unknown, however, whether this genetic profile is accompanied by disturbed macromolecular permeability of systemic capillary endothelium, possibly in the context of generalized endothelial dysfunction. In the present study, the ACE gene polymorphism was determined by PCR in 79 never-treated uncomplicated hypertensive men and 16 normotensive men as controls. Evaluation variables were TERalb (transcapillary escape rate of albumin; the 1-h decline rate of intravenous 125I-albumin, a measure of integrity of systemic capillary endothelium), albuminuria and forearm vasodilation to intra-arterial acetylcholine, an index of NO (nitric oxide)-mediated vasomotion, in addition to a series of sensitive parameters of albumin permeation (blood pressure, metabolic status and smoking habits). Analyses were done by comparing D/D homozygotes with grouped I/D (insertion/deletion) and I/I (insertion/insertion) subjects. TERalb was higher in D/D hypertensives, who had higher albuminuria, more frequent microalbuminuria and comparable forearm responsiveness to intra-arterial acetylcholine. Fasting glucose and insulin, insulin sensitivity, 24-h blood pressure, smoking habits and metabolic parameters did not differ between the two groups. TERalb and urine albumin values were positively associated in the hypertensive subjects. In conclusion, ACE D/D homozygosis, independently of several confounding factors, associates with higher TERalb in men with essential hypertension. This may reflect noxious genetic influences on systemic vascular permeability, a critical control mechanism for atherogenesis in the absence of grossly impaired NO-mediated arteriolar responsiveness. The parallel behaviour of TERalb and albuminuria suggests some shared genetically mediated determinant of renal and systemic microvascular abnormalities in hypertension.

Effect of dietary protein and enalapril on proximal tubular delivery and absorption of albumin in nephrotic rats

In passive Heymann nephritis (PHN), angiotensin-converting enzyme inhibition (ACEI) or a low dietary protein intake decreases albuminuria (UAlbV). Although this reduction in albuminuria appears to result from an improvement in glomerular permselectivity, the effect of these treatments on albumin permeation and absorption by the nephron has not been clarified. This study used micropuncture techniques to examine the effect of these two treatments on albumin permeation (by measuring the delivery of albumin to the proximal tubule) and the tubular absorption of albumin. PHN rats (12-18 days after injection of FX1A) were switched from 23% to either 40% protein diet (HP), 40% protein diet and concomitantly treated with enalapril (40 mg.kg-1.day-1) (HPE), or to 8% (LP) protein diet for 4-6 days. Although left kidney glomerular filtration rate (GFR) did not differ among the groups, UAlbV from the left kidney in LP and HPE was only 20-40% of that observed for the HP group. In protocol 1, the fractional recovery of albumin (FRAlb) in urine was calculated following injection of artificial tubular fluid containing [14C]inulin and 125I-labeled albumin into the earliest identifiable proximal loops. There were no differences in FRAlb among the three groups. In protocol 2, timed quantitative collections of tubular fluid were obtained from proximal tubular loops. The rate of albumin delivery to the earliest accessible loops of the proximal tubule was significantly lower for the LP and HPE groups compared with the HP group. For each group, albumin concentration corrected for water absorption was not altered along the proximal tubule. The data indicate that alterations of dietary protein intake or ACEI treatment results in large changes in the delivery of albumin at the proximal tubule that could singularly account for the changes in urinary albumin excretion.