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Abstract: The renin–angiotensin system (RAS) exercises fundamental control over sodium and water handling in the kidney. Accordingly, dysregulation of the RAS leads to blood pressure elevation with ensuing renal and cardiovascular damage. Recent studies have revealed that the RAS hormonal cascade is more complex than initially posited with multiple enzymes, effector molecules, and receptors that coordinately regulate the effects of the RAS on the kidney and vasculature. Moreover, recently identified tissue-specific RAS components have pleomorphic effects independent of the circulating RAS that influence critical homeostatic mechanisms including the immune response and fetal development. Further characterization of the diverse interactions between the RAS and other signaling pathways within specific tissues should lead to novel treatments for renal and cardiovascular disease. [Copyright &y& Elsevier]

A. H. J. D anserand J. J. S aris. Prorenin Uptake in the Heart: a Prerequisite for Local Angiotensin Generation? Journal of Molecular and Cellular Cardiology (2002) 34, 1463–1472. Interference with locally generated angiotensin II most likely underlies the beneficial effects of renin-angiotensin system blockers in cardiac disorders. Since renin is not synthesized in the heart, this enzyme must be sequestered from the circulation in order to allow angiotensin generation at cardiac tissue sites. This review addresses the various ways through which circulating (i.e., kidney-derived) renin may reach cardiac tissue sites, considering in particular the possibility that prorenin, the inactive precursor of renin, is involved in cardiac angiotensin generation, as the plasma concentrations of prorenin are tenfold higher than those of renin. Renin and prorenin diffuse into the cardiac interstitial space and bind to cardiac (pro)renin receptors/renin-binding proteins. One of these receptors is the mannose 6-phosphate/insulin-like growth factor II receptor. This receptor not only binds mannose 6-phosphate-containing ligands like renin and prorenin, it also internalizes these enzymes, and activates prorenin intracellularly. This process possibly represents (pro)renin clearance, since intracellular angiotensin generation could not be demonstrated following (pro)renin uptake by cardiomyocytes. Angiotensin II-mediated myocyte proliferation did occur when incubating cardiomyocytes with prorenin plus angiotensionogen. The effects of prorenin plus angiotensinogen were comparable to those of 100 nmol/l angiotensin II, although the angiotensin II levels in the medium during exposure of the cells to prorenin plus angiotensinogen were <1 nmol/l. This suggests that cardiac angiotensin II generation by circulating renin occurs predominantly on the cell surface. The presence of ACE and/or renin on the cell membrane, in the microenvironment of angiotensin receptors, would allow maximal efficiency of local angiotensin II generation, i.e., immediate binding of angiotensin II to its receptors with minimal loss into the extracellular space. [Copyright &y& Elsevier]

Angiotensin II and aldosterone are the main effectors of the renin-angiotensin aldosterone system (RAAS) and have a central role in hypertension as well as cardiovascular and renal disease. The localization of RAAS components within the retina has led to studies investigating the roles of angiotensin II, aldosterone and the counter regulatory arm of the pathway in vision-threatening retinopathies. This review will provide a brief overview of RAAS components as well as the vascular pathology that develops in the retinal diseases, retinopathy of prematurity, diabetic retinopathy and neovascular age-related macular degeneration. The review will discuss pre-clinical and clinical evidence that modulation of the RAAS alters the development of vasculopathy and inflammation in the aforementioned retinopathies, as well as the emerging role of aldosterone and the mineralocorticoid receptor in central serous chorioretinopathy. • A local renin-angiotensin aldosterone system exists within the retina. • Angiotensin II and aldosterone promote vascular pathology and inflammation in the retina. • Blockade of renin, the AT1R and ACE reduce retinal vasculopathy and inflammation. • Blockade of aldosterone/MRreduce retinal edema and vasculopathy. [ABSTRACT FROM AUTHOR]