Enrico Niutta

Genetic and experimental hypertension in the animal model-similarities and dissimilarities to the development of human hypertension

In this article, we present the results we have obtained from experimental and genetic models of human essential hypertension, in order to investigate those findings relevant to understanding the time course and the mechanisms underlying the human disease. With experiments on the renal artery constriction in the conscious dog, we have shown that a kidney lesion can produce a form of hypertension not different, in the established phase, from the essential one and that the onset of this form follows a phasic pattern during which the initial stages are crucial for understanding the mechanisms leading to hypertension. We also consider a rat model (MHS) that spontaneously develops a form of hypertension very similar to the human disease. In this model, we have demonstrated by a kidney cross-transplantation experiment and functional studies that the kidney is responsible for the rise in blood pressure and that the organ dysfunction is probably due to a primary abnormality in ion handling of the cell membrane. This cellular alteration, detected both in MHS erythrocytes and in their kidney proximal tubular cells, should be the cause for the higher rate of kidney Na+ reabsorption observed in the MHS. Comparing this animal model with, at least, a subgroup of humans prone to develop hypertension or already hypertensive, it is possible to detect a series of similarities in the kidney function, hormonal pattern, and cellular function of the two species that allows us to argue that the MHS is a suitable model from which to draw conclusions relevant to the pathogenesis of essential hypertension in some humans.

Genetic hypertension and the kidney

The relationship between the kidney and genetic hypertension has been assessed in light of the changes seen in some kidney and cell functions during the phases preceding and accompanying the development of “genetic” types of hypertension in rats and humans. Comparison of the kidney function of normotensive subjects likely to develop hypertension with that of matched controls resistant to hypertension showed, in the former, a higher glomerular filtration rate (GFR), greater tubular reabsorption, larger 24-h urinary output, larger fraction of cardiac output to the kidney, and lower plasma renin activity. After the transplantation of a kidney from a subject in the hypertension-prone group, recipients had higher blood pressure and required more antihypertensive therapy than recipients of kidneys from the hypertension-resistant group. In humans this finding is not as clear as in rats. During the development of hypertension most of these differences in kidney function in the two groups of subjects tend to disappear. The changes in cell function, measured particularly in rats, were consistent with the organ function changes. Cell volume and sodium content were lower, while the transport rate across the cell membrane was faster in proximal tubular cells of rats with genetic hypertension than in the appropriate controls. This is in keeping with the concept of a primary increase in proximal tubular reabsorption leading, on the one hand, to an increase in GFR and renal blood flow and a decrease in renin and, on the other, to an increase in blood pressure. The same differences in proximal tubular cell function were found in the two groups of rats when their red blood cells (RBC) were compared. Genetic analysis and bone marrow transplantation studies showed that the RBC function of genetically hypertensive rats was primarily determined within their stem cells and was genetically linked to hypertension. In view of these two last findings and the similarities between red blood cells and proximal tubular cells, it is suggested that hypertension in rats may be caused by a genetic modification of the membranes of proximal tubular cells. In humans the same mechanisms might be present, but such a proposal remains highly hypothetical.

Pathogenetic mechanisms in essential hypertension. Analogies between a rat model and the human disease

Essential hypertension is a genetic disease. Its phenotypic expression depends on the interaction between genetic and environmental factors. In prehypertensive rats of the Milan hypertensive strain (MHS) a genetically inherited increase of tubular reabsorption was found, which causes the increase of blood pressure. Studies of ion transport systems in these rats have shown that the Na-K cotransport activity is increased both in erythrocytes and in tubular cells of MHS rats compared with their normotensive controls (MNS) and that this alteration is genetically linked to the transmission of high blood pressure levels. Also, in young human normotensives prone to develop essential hypertension there is an abnormal pattern of renal function which could be in agreement with a primitive increase in tubular reabsorption. Studies of erythrocyte ion transport systems in these subjects suggest that at least in a subgroup of humans predisposed to develop essential hypertension a pathogenetic mechanism similar to the one proposed for the MHS rat can be at work.