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Nephrology beyond JASN |
In the past wise rabbis had stated: "The human body was given ten organs of which it is the task of the kidney to provide the human body with thought" (Talmud Brochot). This view of the kidney, although immensely flattering to nephrologists, is no longer universally accepted today. A remaining source of pride in nephrology, however, was the conviction that the kidney was the central, if not unique, player in the genesis of all forms of hypertension.
Richard Bright made the seminal observation that renal disease is associated with left ventricular hypertrophy and presumed hypertension. Since that observation, the kidney has occupied a central role in concepts of the pathogenesis of hypertension even in patients without primary renal disease. Based on experiments and system analysis of Arthur C. Guyton (1,2), it has been commonly accepted that the kidney determined the pressure–natriuresis relationship and thus was of overriding importance for long-term setting of BP in any form of hypertension. This view found some support in cross-transplantation experiments which documented that "BP goes with the kidney": transplantation of the kidney of a hypertensive animal, or even of a genetically hypertension-prone animal, into an immunologically compatible normotensive recipient overrides all regulatory mechanisms, such as volume control, etc., and provokes hypertension in the recipient. Conversely, transplantation of the kidney of a normotensive donor causes normotension in a hypertensive recipient (3). The latter has also been unequivocally shown in human kidney transplantation (4). Remarkably, however, in the transplantation experiments the results did not unequivocally support the sodium retention hypothesis of Guyton and several other proposed pathomechanisms. The authors wisely concluded that "none of the investigated mechanisms was altered in a way that might help to explain the rapid and consistent development of hypertension in the kidney recipients" (3). Both structural abnormalities of the kidney, e.g., nephron underdosing as postulated by Brenner (5) and proven by Keller (6), and functional renal abnormalities, as recently reviewed by Johnson (7), have been incriminated to explain the primacy of the kidney in the genesis of hypertension. It is also of note that practically all monogenic forms of hypertension are characterized by modified renal sodium transport and sodium balance (8).
The complacent view that the kidney was the center of the hypertension universe has been given a substantial blow by the study by Crowley and colleagues. The results challenge the hypothesis that abnormal BP is exclusively the result of intrinsic changes of kidney function as assumed in the past and document that extrarenal tissues, e.g., vascular system, central nervous system, or others, make nonredundant contributions to BP regulation. The authors have an impressive track record in the use of mice with genetically modified renin-angiotensin systems (RAS) (9). How did they tackle the problem this time? They reasoned that angiotensin receptors (AT1) are ubiquitously expressed, not only in the kidney (10), but also in extrarenal tissues. To elucidate the relative contributions of renal and extrarenal tissues to BP regulation they adopted the technically demanding cross-transplantation strategy that had previously been used successfully in rat studies by others (11). The mouse AT1A receptor is roughly equivalent to the human AT1 receptor. Crowley studied donor-recipient combinations using AT1A deficient mice and their wild-type littermates respectively. BP and plasma renin were studied in the following four combinations:
BP was assessed with the methodological gold standard of implanted radiotelemetry transmitters.
The expected findings were unchanged BP values in the first group, confirming technical success and low BP in the second group. The latter finding demonstrates that absence of a functionally fully active RAS interferes with maintenance of a normal BP—no surprise.
The surprise came with group 3: If the AT1A receptor was knocked out in the recipient animal, even transplantation of a wild-type donor kidney that expressed the AT1A receptor did not restore normal BP. In other words, restored AT1A signaling in the kidney blood did not normalize systemic BP in the AT1A deficient recipient. The result undoubtedly forces believers in the Guyton dogma to revise, or rather to modify, the orthodox concept. The findings are evidence that extrarenal vascular territories make nonredundant contributions to BP regulation, i.e, a normal AT1A-expressing kidney cannot nullify the BP effects of functionally deficient AT1A signaling in the extrarenal vascular territories. The authors performed appropriate ancillary studies to exclude the possibility that lower aldosterone generation had been responsible for the unanticipated low BP in group 3: Administration of aldosterone failed to normalize BP in the recipient with deficient AT1A signaling in the extrarenal vasculature.
The study does not provide information regarding which extrarenal system is the culprit and how the effect on BP is mediated, e.g., excess vasodilatory or inappropriate vasoconstrictor mechanisms. The RAS is a system of admittedly overriding importance for BP regulation, but other systems and mediators may also play a role. There will be surprises, as illustrated by the recent demonstrations of novel vasodilatory factors in periadventitial fat (12) or vasoconstrictive factors in endothelial cells (13).
After evidence for abnormal organogenesis had been found in the kidneys of patients with essential hypertension (5,6), the question arises: Is there evidence of intrinsic structural abnormalities in the extrarenal vasculature as well? At least experimentally, an intrinsic abnormality of vascular smooth muscle cells of resistance vessels is suggested by the finding of narrowed preglomerular arterioles in prehypertensive spontaneously hypertensive rats (14). While such information on resistance vessels in prehypertensive humans is not available, there is at least information on rarefication of skin capillaries: This is found not only in patients with essential hypertension (15), but even in normotensive offspring of parents with essential hypertension (16). Thus there is a vague hint for abnormalities in extrarenal vasculature preceding hypertension.
Is the kidney the only culprit in any form of hypertension and is it always responsible for hypertension? According to the study of Crowley, it certainly is not.
One result of the study undoubtedly will be that new candidate mechanisms and new candidate genes will have to be considered and investigated in the future.
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Address correspondence to: Prof. Eberhard Ritz, Department Internal Medicine, Division of Nephrology, Bergheimer Strasse 56a, D-69115 Heidelberg, Germany. Phone: a49-0-6221-601705 or a49-0-6221-189976; Fax: a49-0-6221-603302; E-mail: Prof.E.Ritz{at}t-online.de
References
The rapidly evolving field of the APJ receptor and its cognate agonist apelin has recently been given a new twist by the demonstration of Boucher et al. (1) that apelin is synthesized by human white fat cells in an insulin- and obesity-dependent fashion. This finding makes apelin a substance of great interest given the variety of actions, including potent cardiovascular actions, of this peptide. The unraveling of the apelin story beautifully illustrates the power of modern molecular techniques. To fully appreciate the implications of the study of Boucher et al. (1), some background information is helpful.
The APJ receptor had originally been identified as an angiotensin receptor–like molecule with seven transmembrane domains (3). Human HIV-1 virus enters CD4+ cells by engaging CCR5 and CXCR4 receptors (2). It was noted that APJ serves as a further co-receptor (4), which allows a subset of HIV-1 isolates to enter T lymphocytes (5) and neural cells (6). Because the agonist was originally unknown, the receptor had been classified as an orphan receptor. Using ingenious novel techniques, Tatemoto et al. (7) very soon isolated the cognate endogenous peptide ligand for the APJ receptor, which was given the name apelin. Coexpression of apelin and the G-protein–coupled APJ receptor was documented in several tissues, including the brain (8). The gene identified by Tatemoto et al. (7) predicted a 77 amino acid peptide, known as proapelin. In different tissues it is cleaved into what is thought to be the main physiologically active form, apelin-36, and into further active moieties such as apelin-13 and apelin-12 (7,9).
What is known about the functions of apelin? It soon emerged that apelin has potent cardiovascular actions. It causes hypotension and is a strong cardiac inotropic agent. In endothelial and vascular smooth muscle cells of human large conduit vessels as well as in cardiomyocytes of the human hearts, APJ immunoreactivity is found, while apelin immunoreactivity was noted in the secretory vesicles and Golgi apparatus of endothelial cells. This constellation suggested a role of apelin as a paracrine cardiovascular regulator (7,10). Because both proapelin and apelin-36 are demonstrable in the circulation as well, an additional role as an endocrine agent is also conceivable, however (11). Apelin potently reduces BP (12,13); the hypotensive effect is abrogated by inhibition of nitric oxide. In APJ knock-out mice, the hypotensive effect of apelin is also absent and the pressor response to angiotensin II (AngII) is increased, suggesting that one of the actions of apelin is to counteract the pressor effect of AngII (13). BP increases both after intravenous and intracerebroventricular injection of apelin, but more so after intracerebroventricular injection (14). After intraperitoneal injection of the known inotrope apelin (15,16), LV preload, LV afterload, and contractile reserve are significantly reduced (17). Against this background, the results of microarray studies before and after LV assist devices in patients with heart failure are of interest. Transcriptional profiling showed that the gene most significantly upregulated by cardiac unloading was the apelin receptor APJ (14).
Apart from the fact that apelin is localized in and acts on the cardiovascular system, it is of interest to the nephrologist that it is also colocalized with arginine vasopressin in the supraoptic and periventricular nuclei (18), functioning as a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin release and also influencing drinking behavior (19).
What are the new aspects provided by the study of Boucher et al. (1)?
The first novel information is the finding that apelin is expressed and secreted by human and murine adipocytes of white, but less so of brown, fat, in line with past findings in the rat (9). The level of expression is comparable to that in organs known so far to express apelin, such as the heart. Second, and perhaps more importantly, when different models of obesity were studied in mice, the most impressive increase of apelin expression in fat cells and increase in apelin concentrations in plasma was seen in models characterized by hyperinsulinemia, suggesting that it is insulin, and only to a lesser extent obesity per se or dietary fat, that are important for the regulation of apelin. Conversely, low insulin concentrations in streptozotocin diabetic mice were associated with less apelin expression in fat cells. Apelin expression was strongly reduced by fasting and rescued by refeeding. The human relevance of this observation was documented by the finding that both insulin and apelin concentrations were elevated in obese patients. Incubation of adipocytes with insulin yielded half-maximal effective concentrations of insulin well in the range of the insulin concentrations required for other typical insulin effects. The finding suggests that insulin influences blood levels of apelin, identifying apelin as a novel adipocyte endocrine secretion with potential repercussions on the understanding of the link between obesity, hyperinsulinemia, and cardiovascular complications.
The authors have added another player to a growing list of adipokines. Some adipokines, e.g., leptin, plasminogen activator inhibitor–1, resistin, and SPARC (secreted protein acidic and rich in cysteine), have already been shown to be influenced by insulin, and the authors have added another one. In view of its powerful cardiovascular effects, the question arises whether apelin plays a role, perhaps compensatory, in the genesis of cardiovascular complications of hyperinsulinemic obesity. Apelin is also expressed in the kidney (9), but information on apelin in renal disease and its concentration in patients with impaired renal function is not yet available. But the field is moving rapidly—stay tuned!
References
It is textbook knowledge, but has recently been well documented by prospective trials (1), that obesity, as an important aspect of the metabolic syndrome, is one of the major risk factors for hypertension (2,3) and for renal disease (4). It had recently been argued that fat cells express the AT1 angiotensin receptor and that angiotensin II (AngII) promotes the differentiation of preadipocytes into adipocytes (5), thus reducing the risk of type 2 diabetes. This proposal seems at first sight to be counterintuitive, because this situation should lead to more fat tissue. Why should more fat tissue be less diabetogenic? It has recently become apparent that, with respect to diabetogenic risk and metabolic profile, substantial differences exist between subcutaneous and visceral fat. Removal of subcutaneous fat by liposuction failed to change insulin sensitivity (6). This also explains the apparent paradox of less diabetes despite more fat tissue, though the metabolically less adverse subcutaneous fat tissue after administration of glitazones. Fat tissue is much more complex and heterogeneous than previously thought and holds surprises with respect to the renin-angiotensin system (RAS) as well.
Since the classical work of Messerli et al. (7), it has been repeatedly confirmed (8,9) that in obese individuals the concentrations of angiotensinogen, renin, aldosterone, and angiotensin-converting enzyme (ACE) in the circulation are increased. Furthermore, in obese patients the expression of the angiotensinogen gene was found to be higher in visceral than in subcutaneous adipocytes (10,11)—but all these findings were obtained in observational studies and are thus susceptible to potential confounding.
This problem was circumvented in the study by Engeli et al. by a prospective design: The authors examined postmenopausal women with stable obesity, of whom 17 achieved 5% weight reduction after starting a weight reduction protocol. Abdominal subcutaneous adipose tissue was obtained by biopsy before and after weight reduction, as were ambulatory BP, homeostatic model assessment (HOMA) index to evaluate insulin sensitivity, and RAS parameters in the blood.
As compared with lean controls, obese menopausal women had increased plasma concentrations of angiotensinogen, renin, aldosterone, and ACE, confirming the previous studies. In adipose tissue the angiotensinogen message (AGTmRNA/GAPDH) was decreased, but the effect on overall synthesis of angiotensinogen has to be cautiously interpreted in view of the overall increase of total fat mass.
The key finding was that weight loss of >5% within 16 wk lowered the concentrations of angiotensinogen, renin, aldosterone, and ACE to levels approaching those in lean controls. The decrease of angiotensinogen was not significantly correlated to the reduction of body mass index (as an index of overall fat), but to the reduction of waist circumference (as an index of visceral fat). The decrease of plasma angiotensinogen concentration was paralleled by a significant decrease of angiotensinogen gene expression in (subcutaneous) fat tissue. The reduction of 24-h systolic BP by 7 mmHg was significantly correlated with the reduction of plasma angiotensinogen concentration and angiotensinogen expression in fat tissue.
The study illustrates the importance of human studies, because studies in obese rodents had uniformly found higher angiotensinogen expression in fat tissue of obese animals (12–16). Obviously humans are a poor model for the rat. Of equal importance, the study shows that angiotensinogen expression by fat cells decreases after weight reduction. Although concomitant reduction of angiotensinogen synthesis and secretion by the liver has not been firmly excluded, it is plausible to assume that it is adipocyte generated angiotensinogen that is responsible, particulary because animal experiments have documented that angiotensinogen from fat cells enters the circulation (12).
A further interesting aspect is the increased renin and aldosterone concentrations in obese compared with lean women—clearly inappropriate to sodium retention and elevated BP. The authors ascribed this with good reason to sympathetic overactivity, which in obese subjects might be the consequence of increased leptin concentrations (17).
Why are these observations clinically relevant? It has been correctly stated that obese hypertensive patients were in the past systematically excluded from controlled trials on antihypertensive agents. Furthermore, aspects of the management specific for obese hypertensive patients have largely been omitted from current guidelines (18). To illustrate the need for more specific information let us just consider that 
-blockers make weight loss more difficult and that thiazides increase the risk of diabetes. There is no question that BP is more difficult to control in the obese, that BP is more salt-sensitive, and that pharmacokinetics of many antihypertensives are altered.
In the context of the article by Engeli et al., the question arises whether blockade of the renin angiotensin system is a good therapeutic strategy in the hypertensive obese patient. We need definite data from intervention trials, but there would be many plausible arguments for this proposal. Just to mention two pertinent recent findings: In an experimental model of the metabolic syndrome, AT1 receptors are upregulated (19); and, particularly exciting from a nephrological perspective (20), temporary blockade of the renin angiotensin system in obese rats with the metabolic syndrome definitely reduced renal damage when diabetes mellitus had finally supervened. These examples illustrate just how urgent it is to clarify whether, in obese hypertensive patients with a high risk of diabetes, of whom a large proportion is destined to end up in the care of a nephrologist (21), one can obtain specific benefit by blocking the RAS.
References
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