Angiotensin II and Cardiovascular-Renal Remodelling in Hypertension: Insights from a Human Model Opposite to Hypertensio
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REVIEW ARTICLE
Angiotensin II and Cardiovascular-Renal Remodelling in Hypertension: Insights from a Human Model Opposite to Hypertension Verdiana Ravarotto1 • Elisa Pagnin1 • Antonio Fragasso1 • Giuseppe Maiolino1 Lorenzo A. Calo`1
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Received: 7 January 2015 / Accepted: 4 March 2015 Ó Springer International Publishing Switzerland 2015
Abstract Insights into the Angiotensin II (Ang II) signalling pathways have been provided by extensive studies using Bartter’s/Gitelman’s syndromes patients. These syndromes are characterized by activation of the reninangiotensin-aldosterone system but do not develop hypertension and cardiovascular remodelling, therefore represent a mirror image of hypertension and clinically manifest themselves as the opposite of hypertension. The short and the long-term signalling of Ang II remain an important matter of investigation to shed light on mechanisms responsible for the pathophysiology of hypertension and its long-term complications, such as cardiovascular remodelling and atherogenesis. In particular the long-term signalling of Ang II is involved in the pathophysiology of cardiovascular-renal remodelling, inflammatory and hypertrophic responses in which the relationship between RhoA/Rho kinase pathway and NO system plays a crucial role. This review reports the results of our studies in Bartter’s and Gitelman’s syndromes to get better insight these processes and the role of Ang II signaling. The information obtained from the studies in Bartter’s/Gitelman’s patients can, in fact, clarify, confirm or be used to gather more general data on the biochemical mechanisms responsible for the pathophysiology of hypertension and its long-term complications and could contribute to identify additional potential significant targets of therapy.
& Lorenzo A. Calo` [email protected] 1
Department of Medicine, Nephrology and Hypertension, University of Padova, Via Giustiniani, 2, 35128 Padua, Italy
Keywords Rho kinase Nitric oxide Angiotensin II signaling Gitelman’s syndrome Bartter’s syndrome Cardiovascular-renal remodeling
1 Introduction Angiotensin II (Ang II) signaling is central in the control and regulation of vascular tone and, in general, in cardiovascular-renal physiology and pathophysiology [1–3]. Persistent activation of the renin-angiotensin-aldosterone system (RAAS) in healthy individuals leads to hypertension and target organ damage [4]. Despite the increases in the signaling molecules associated with activation of the pressor systems that induce hypertension and its long term complications, Bartter’s and Gitelman’s patients exhibit normotension or hypotension. Bartter’s and Gitelman’s patients have normal Ang II receptor number and affinity [5, 6] and activated RAAS, but show clinical signs related to abnormal RAAS activation, suggesting that in these patients Ang II signaling is blocked or interrupted at postreceptor level. This further suggests a condition wherein the countervailing signals that oppose RAAS are, in Bartter’s and Gitelman’s patients, activated and thus are a
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