Angiotensin, high blood pressure and glomerular autoregulation

In this issue of the journal, Inscho et al. [1]. demonstrate that isolated kidney preparations from rats made hypertensive with infusions of subpressor doses of angiotensin II (for 10 or 14 days) lose their capability to respond to changes of blood pressure, and therefore to properly control glomerular haemodynamics. The angiotensin II model is reminiscent of the widely used (in the 1960s and 1970s) ‘two kidneys, one clamp Goldblatt rat', in which increased production of renin by the clamped kidney leads to hypertension (after approximately 3 weeks) and to exaggerated natriuresis [2], a phenomenon that depends on the inability of the unclamped kidney to regulate intraglomerular pressure [3]. For several years, one question remained unanswered, namely how important are the pro-hypertensive actions of the renin–angiotensin system with respect to functional and structural changes of the cardiovascular system and kidney autoregulatory behaviour in hypertension. Indeed, hypertensive patients endure an almost eight-fold greater risk of progressing to end-stage renal failure compared to normotensive individuals [1]. A better knowledge of factors that cause impairment of renal autoregulation appears to be of great importance. The results presented by Inscho et al. [1] may provide some insight. Treatment with an antagonist of the AT-1 receptor, to counteract angiotensin II, or with a triade of antihypertensive agents to control blood pressure, reduce or prevent the increase of blood pressure and restore or maintain autoregulation. The authors suggest that high blood pressure is the primary cause of the autoregulation decline. The protracted action of angiotensin II on its receptors throughout the body, and in the kidney, appears to be relevant (in terms of autoregulation decline) only for its ability to increase blood pressure. Such a conclusion is supported by data in the literature showing that autoregulation of renal blood flow is impaired (i) in the kidneys of hypertensive rats obtained by genetic selection (spontaneously hypertensive rat), or (ii) by treatment with nitro-l-arginine methyl ester, an inhibitor of NO synthase that reduces production of NO from endothelia and other tissues. In these two models, the renin–angiotensin system is not the primary cause of hypertension (see references quoted in Inscho et al. [1]). The authors conclude that (i) high blood pressure is dangerous; (ii) it must be controlled; and (iii) treatments will be beneficial if they maintain stable normotensive values of blood pressure and optimal renal autoregulation. This is in accordance with the conclusions of recent clinical comparisons of several antihypertensive agents in large populations of hypertensive patients. In several clinical trials, it has been found that, under effective antihypertensive treatments (with angiotensin-converting enzyme inhibitors, calcium antagonists and diuretics), the beneficial outcomes are equivalent [4,5]. For a less empirical approach to therapy, the identification of a target tissue and, eventually, the cellular element that might be instrumental in kidney autoregulation, as well as knowledge of how high blood pressure may insult such a target, is desirable. Recent data suggest that the target tissue comprises the pre-glomerular arterial vessels (preGA) and the target cell could be the endothelium. When blood pressure increases, the preGA contract to reduce flow and intraglomerular pressure. When blood pressure decreases, the preGA eventually relax and the postGA contracts to maintain intraglomerular pressure and filtration. This process is peculiar to the kidney and is sometimes indicated by the term ‘autoregulation of glomerular function'. The question of how high blood pressure may disrupt the autoregulatory behaviour of the preGA and, more generally, of large and small arteries throughout the body, was eventually addressed by studies intending to elucidate new functions and roles of the endothelium. The endothelial cell is continuously exposed to mechanical stimuli that modulate the production of numerous agents, both vasodilators [e.g. NO, prostaglandins (PG), endothelium-derived hyperpolarizing factor (EDHF), kinins, adenosine] or vasoconstrictors (reactive oxygen species, endothelins, and others). In normal conditions, a balance between generation and release of vasodilators and vasoconstrictors maintains optimal endothelial reactivity, vascular smooth muscle tone and the integrity and architecture of the vessel wall. It is known that mechanical stimuli of two types [6] are exerted on the preGA endothelium (especially in the presence of high blood pressure) through ‘a viscous drag that is generated at the luminal surface of the endothelial cells by the streaming blood (wall shear stress) and the cyclic strain of the vascular wall that results from pulsatile changes of blood pressure’ [7]. Endothelia sense changes in pressure through mechanoreceptors (ion channels, other membrane sensors) that have connections with the cytoskeleton and translate signals to the cytoplasma and the nucleus. Generation and release of bioactive molecules (see above), in addition to modulation of functional components of the endothelial plasma membrane that may be increased or inhibited by the wall shear stress, modulate and possibly alter the endothelium activities and their influence in the adjacent smooth muscles or the neighbour endothelial cells and, eventually, the blood elements that make contact with the endothelium. In this way, the endothelium controls tonus and contractility of the arterial smooth muscle, preserves the integrity and intimate structure of the vessel wall and interacts with circulating blood elements. This complex network undergoes fine regulation which, when altered, may reduce the contractility of arteries (especially the preGA) through disfunction of the endothelium or smooth muscle, or even via structural changes in the vessel wall. Little is known about the factors or agents that may be responsible for the reduction of reactivity in the preGA and future studies should focus on understanding the mechanism by which the vessel wall, when submitted to high pressure, loses its ability to control renal blood flow. Other autacoids that have not been mentioned above, but which may be relevant in the context of the present analysis, are the angiotensins, the kinins and their receptors. In the work by Inscho et al. [1], the preGA lesion that is caused by high blood pressure is reduced by treatment with an AT-1 antagonist. However, Inscho et al. [1] do not attempt to explain how and where this type of antihypertensive agents could act. From recent reports, it emerges that the mechanism of action of the AT-1 antagonists may be more complex than was initially thought. Blockade of AT-1 increases (by feedback) renin secretion and angiotensin production, which may reach levels sufficient to activate the AT-2 receptor present in the endothelium. As demonstrated recently [8], the AT-2 receptor mediates the production of bradykinin locally in the endothelium compartment and may restore optimal endothelial functions [9]. Bradykinin is the only agent known to promote formation and release of NO, prostacyclin and EDHF, depending on the vessel and vessel species, and also to inhibit the release of endothelins. Such multiple effects are apparently instrumental for maintaining optimal endothelial functions not only by contributing to vessel dilatation, but also by preventing (in normal conditions), or eliminating (after exposure to high blood pressure), the still unknown lesions that are responsible for reducing preGA contractility in response to high blood pressure. Again, this topic is likely to become a challenge for future investigations. Despite its value and originality, the work described by Inscho et al. [1] has some limitations and is not exempt from criticism. Preventing an increase in blood pressure induced by angiotensin II, from the beginning, through an antihypertensive therapy is an experimental condition that has no counterpart in the clinic. Conversely, treatment with the AT-1 antagonist better reflects the case of hypertensive patients who are submitted to treatment only when blood pressure has reached hypertensive values. A careful analysis of data obtained with the two protocols, in which the hypertension induced by angiotensin II was treated with the AT-1 antagonist, reveals differences that have not been discussed by the authors. In the 10-day experiment, treatment with the antagonist restores contractility of preGA, but not the ability to relax when pressure is reduced: in the 14-day experiment, the opposite occurs and only the dilatation of the preGA returns to normal. This finding is surprising and unexplained. Moreover, restoration of autoregulatory behaviour in the arteries of animals perfused with angiotensin II for 14 days is not consistent with the authors interpretation, and raises the question of what could happen if the angiotensin II infusion was prolonged for 3–4 weeks. Would the preGA lesion become permanent and irreversible? The results of the study are therefore not as fully conclusive as the authors claim, and more experiments will be needed to elucidate further the deleterious effects of angiotensin.