Selective renin inhibition in obese hypertensive patients

One of the extraordinary recent discoveries related to the renin–angiotensin system was represented by the finding that the renin–angiotensin system includes, along with a systemic circulatory component, many tissue subcomponents synthesized at the level of different organs, including the heart, the kidney, the vasculature and the adipose tissue [1,2]. In those clinical conditions characterized by renin–angiotensin system activation, such as obesity-associated hypertension, locally generated angiotensin II, but also renin and prorenin as well, exert several pro-atherogenic effects. In such a context, the development of clinically effective renin inhibitors represents the most advanced pharmacological approach in cardiovascular disease. Aliskiren is the first orally active direct renin inhibitor recently approved for the treatment of hypertension [3]. This compound blocks the generation of angiotensin I from angiotensinogen, the initial and rate-limiting step of the renin–angiotensin system, by inhibiting the active enzymatic site of renin. Moreover, the drug inhibits renin and activated prorenin when bound at the (pro)renin receptors [4]. The long pharmacological half-life of aliskiren makes this drug suitable for once-daily administration, with blood pressure-lowering effects that persist for a considerable period following the drug discontinuation. It's peculiar multiple mechanisms of action might provide to aliskiren an additional potential opportunity to interrupt the tissue renin–angiotensin system-related metabolic changes. Of note, this possibility requires an ability of aliskiren to reach sufficiently high and prolonged tissue concentrations such as to achieve a full inhibition of the local renin–angiotensin system components. In the present issue of the Journal of Hypertension, Boschmann et al.[5] investigate whether chronic aliskiren administration (at a single daily dosage of 300 mg) is capable of attaining concentrations in the adipose tissue and in the skeletal muscle sufficient to inhibit the local renin–angiotensin system activity in essential hypertensive patients complicated by visceral obesity. In this pilot, open-label study, drug concentrations and renin–angiotensin system biomarkers were assessed in the interstitial fluid using the microdialytic procedures and in biopsies from the abdominal subcutaneous adipose tissue and in the skeletal muscle. The novel aspect of this elegant study is the demonstration that, after 4 weeks of administration, aliskiren is detectable in all body compartments investigated, including adipose and skeletal muscle tissues, and that the levels reached are capable of inhibiting tissue angiotensin II concentrations. Of note, aliskiren was still detectable in tissue biopsies 8 weeks after discontinuation. The article by Boschmann et al.[5] is methodologically of high quality. Although being a pilot report conducted in a limited number of patients, the study provides new intriguing data and information that are encouraging for the clinical utilization of aliskiren and stimulate future perspectives of research. Some aspects of this interesting report deserve further comments. A first consideration concerns the appropriate clinical model, that is, the obese hypertensive patients, employed in this study. Obesity is strongly associated with hypertension. As recently reviewed by Mathieu et al.[6], adipose tissue represents an extra source of angiotensinogen, which contributes to the hypertension-related activation of the renin–angiotensin system. In addition, adipocytes express angiotensin II type 1 receptors, whose stimulation by angiotensin II allows the differentiation of pre-adipocytes into mature dysfunctional adipocytes. As a result, mature adipocytes increase their production of pro-inflammatory cytokines and nonesterified free fatty acids, and reduce the amount of adiponectin, leading to an inhibition of skeletal muscle glucose utilization and insulin resistance development. This picture is further complicated by the evidence that angiotensinogen is overexpressed within mature adipocytes, thus guaranteeing a vicious circle between the renin–angiotensin system and the adipose tissue in obese hypertensive patients. Of importance, a large body of literature highlights also a direct crucial role of the renin–angiotensin system in modulating insulin sensitivity. Particularly, angiotensin II is able to stimulate the NADPH oxidase-driven reactive oxygen species production, which in turn exerts inhibiting effects on the PI 3-kinase-Akt signaling pathway and on the glucose transporter GLUT-4 biosynthesis, thus antagonizing the major steps of insulin signaling and glucose transport within the skeletal muscle cells [7]. Taken together, these findings underline a complex interplay among adipocytes and the renin–angiotensin system that characterizes the obesity–hypertension association, thus representing a continuous flame that lights the fire of insulin resistance and its complications. These findings represent the background for the evidence that a long-lasting penetration at the level of adipose and skeletal muscle tissues by aliskiren, as documented by Boschmann et al.[5], might interrupt such reciprocal pathways, providing promising adjunctive multiple benefits in obese hypertensive patients. In line with this hypothesis, aliskiren was able to improve systemic insulin sensitivity, skeletal muscle insulin metabolic signaling and glucose transport in a transgenic rodent model of tissue renin overexpression [8]. More recently, Marchionne et al.[9] showed that aliskiren dramatically improved glucose tolerance and whole-body insulin sensitivity in insulin-resistant obese Zucker rats, an effect associated with an upregulation of insulin action on skeletal muscle glucose transport and of Akt signaling. It is clear that the results of the study by Boschmann et al.[5], together with the metabolic benefits of aliskiren in animal models, although corroborating our understanding of the critical role of the tissue renin–angiotensin system in the cardio-metabolic syndrome, at the same time opens up new research perspectives with aliskiren in humans. Another aspect raised by the present study concerns the clinical relevance of the long-lasting tissue penetration of aliskiren in such patients. Obesity is a recognized major cause of resistant hypertension. If considering that almost 75% of obese patients develop hypertension, it is not surprising that in our clinical practice a poor blood pressure control emerges, as largely documented [10,11]. Interestingly, the authors of the present study previously documented that once-daily aliskiren administration represents an effective choice for hypertensive patients with obesity who fail to achieve blood pressure control with thiazide diuretic treatment [12]. It is conceivable that the prolonged tissue penetration of aliskiren represents a likely explanation of the high effectiveness and tolerability of this compound in this clinical condition, with a promising extended clinical utilization of aliskiren to resistant hypertension. Along with these merits, the article encompasses a number of potential limitations, some of which are of a methodological nature. For example, the behavior of aliskiren in another key tissue characterizing the obese population, that is, the visceral fat, still remains largely undefined. Moreover, whether and to what extent its prolonged tissue deposition might be also detectable in the nonobese hypertensive population requires further studies. Finally, the methodology utilized to detect interstitial angiotensin II concentrations forced the authors to pool samples from several patients. For these reasons, the results of the present study require caution in their interpretation and do not allow conclusive insights on tissue deposition of aliskiren in hypertensive populations. In conclusion, future studies are needed to establish in humans whether aliskiren, in addition to its blood pressure-lowering effects, is the ideal antihypertensive pharmacological agent to counteract the above-mentioned metabolic abnormalities, which characterize the obese hypertensive patient. In the meantime, the present study provides support for considering the tissue renin–angiotensin system as a target of the therapeutic intervention aimed at improving both blood pressure regulation and insulin action in conditions of obesity-related hypertension. ACKNOWLEDGEMENTS Sources of funding: none. Conflict of interest There are no conflicts of interest.