Abstract
ABSTRACTAlthough there is a general agreement on the recommendation for reduced salt intake as a public health issue, the mechanism by which high salt intake triggers pathological effects on the cardio-renal axis is not completely understood. Emerging evidence indicates that the renin-angiotensin-aldosterone system (RAAS) is the main target of high Na+ intake. An inappropriate activation of tissue RAAS may lead to hypertension and organ damage. We reviewed the impact of high salt intake on the RAAS on the cardio-renal axis highlighting the molecular pathways that leads to injury effects. We also provide an assessment of recent observational studies related to the consequences of non-osmotically active Na+ accumulation, breaking the paradigm that high salt intake necessarily increases plasma Na+ concentration promoting water retention
Highlights
Angiotensin II (Ang II), which is generated via angiotensin I (Ang I) cleavage by angiotensin converting enzyme (ACE),[7,8] acts via two main receptors: angiotensin receptor type 1 (AT1R), which induces vasoconstriction, anti-natriuresis, anti-diuresis, vasopressin and aldosterone release, fibrosis and cellular proliferation, while angiotensin receptor type 2 (AT2R), which counterbalances these effects.[9,10]
In male spontaneously hypertensive rats (SHR) under normal salt (0.3%), low salt (0.03%), or high salt diet (HSD) (3%), it was observed that HSD induced glomerular hypertrophy and proteinuria, with a decrease in ACE2 expression, whereas low salt diet (LSD) attenuated renal dysfunction and proteinuria due to a decrease in ACE/ACE2 protein and activity ratio within the kidney mediated by increased cubilin expression.[31]
Information on the impact of salt intake on the course of heart and kidney disease is still unclear but it indicates that the cornerstone for tissue inappropriate activation of renin-angiotensin-aldosterone system (RAAS) is the ACE/ACE2 ratio, leading to augmented local Ang II and AT1R activation
Summary
The renin-angiotensin-aldosterone system (RAAS) regulates essential functions in the organism, such as the maintenance of arterial blood pressure, Na+, and water balance.[1,2] The systemic RAAS is activated when renin secretion in the juxtaglomerular apparatus of the kidney is stimulated by (1) renal artery hypotension, (2) decrease in the Na+ load delivery to the distal tubule that is sensed by the macula densa, and (3) activation of the sympathetic nervous system activity in response to decreased arterial blood pressure.[3,4,5] In the classic view of the RAAS, renin cleaves angiotensinogen (AGT) produced by the liver, generating angiotensin I (Ang I).[6]Angiotensin II (Ang II), which is generated via Ang I cleavage by angiotensin converting enzyme (ACE),[7,8] acts via two main receptors: angiotensin receptor type 1 (AT1R), which induces vasoconstriction, anti-natriuresis, anti-diuresis, vasopressin and aldosterone release, fibrosis and cellular proliferation, while angiotensin receptor type 2 (AT2R), which counterbalances these effects.[9,10] Different Ang II-derived peptides, enzymes, receptors, and routes for Ang II degradation are emerging, supporting the view of different forms of regulation within the system itself.[11]. The cardio-renal axis is of particular interest since it contains all components of the RAAS (tissue or local RAAS), especially the main
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