Intracardiac and Intrarenal Renin-Angiotensin Systems: Mechanisms of Cardiovascular and Renal Effects

Abstract

The renin-angiotensin system (RAS) is a hormonal system that controls body fluid volume, blood pressure, and cardiovascular function in both health and disease. Various tissues, including the heart and kidneys, possess individual locally regulated RASs. In each RAS, the substrate protein angiotensinogen is cleaved by the peptidases renin and angiotensin-converting enzyme to form the biologically active product angiotensin II, which acts as an intracrine cardiac and renal hormone. The components of each RAS, including aldosterone (ALDO), may be produced locally and/or may be delivered by or sequestered from the circulation. Overactivity of the cardiac RAS has been associated with cardiac diseases, including cardiac hypertrophy due to volume and/or pressure overload, heart failure, coronary artery disease with myocardial infarction, and hypertension. Overactivity of the renal RAS has been associated with various kidney diseases, including nephropathies and renal artery stenosis. The principal effects of an overactive RAS include the generation of reactive oxygen species, which leads to "oxidative stress," activation of the nuclear transcription factor kappaB, and stimulation of pathways and genes that promote vasoconstriction, endothelial dysfunction, cell hypertrophy, fibroblast proliferation, inflammation, excess extracellular matrix deposition, atherosclerosis, and thrombosis. It has been suggested that oxidative stress is the central mechanism underlying the pathogenesis of RAS-related and ALDO-related chronic cardiovascular and renal tissue injury and of cardiac arrhythmias and conduction disturbances.

Mechanisms and Modulation of Oxidative/Nitrative Stress in Type 4 Cardio-Renal Syndrome and Renal Sarcopenia

“…ROS such as O2 ·− and H 2 O 2 activate NF-kB, which is inactive in the cytoplasm of normal cells, including renal cells, endothelial cells, smooth muscle cells, cardiac myocytes, etc. (Raizada et al, 2007 ). Activated NF-kB upregulates endothelin production and genes encoding proteins involved in apoptosis, cell growth (e.g., fibroblast growth factors [FGFs], transforming growth factor-beta [TGF-β], platelet-derived growth factors [PDGF], vascular endothelial growth factor [VEGF], etc.…”

“…Chronic inflammation is thought to be the most common result of the elevated oxidative/nitrative stress in CKD as a consequence of the activation of nuclear factor-kB (NF-kB) and other transcription factors regulating the gene expression of pro-inflammatory cytokines and chemokines (Jin Jung et al, 2013 ; Tucker et al, 2015 ; Wu et al, 2016 ; Duni et al, 2017 ). Moreover, both oxidative/nitrative stress and inflammation can amplify each other (Raizada et al, 2007 ; Jin Jung et al, 2013 ; Tucker et al, 2015 ; Wu et al, 2016 ; Duni et al, 2017 ). On the one hand, elevated oxidative/nitrative stress stimulates recruitment and activation of leukocytes, the formation of pro-inflammatory oxidized lipids, advanced protein oxidation products, and advanced glycation end products (AGEs) (Duni et al, 2017 ).…”

“…(Raizada et al, 2007 ). Moreover, NF-kB could upregulate the iNOS gene resulting in excessive NO production which easily forms ONOO − reacting with O2 ·− (Raizada et al, 2007 ).…”

JAK-STAT and the renin-angiotensin system

“…Indeed, experiments in gene-targeted mice demonstrate that kidney-specific Ang II elevation induces high blood pressure, 8 the development of renal inflammation and fibrosis 9 . Further, renal RAS overactivity is associated with the development of various renal pathological processes including glomerular sclerosis, diabetic nephropathy and renal artery stenosis 10 - 12 . Thus, the elucidation of the regulating mechanisms of the intrarenal RAS is a potential new area for development of novel strategies for organ-specific intervention and treatment of hypertension and RAS-associated tissue injury.…”

Modulation of renal oxygenation and perfusion in rat kidney monitored by quantitative diffusion and blood oxygen level dependent magnetic resonance imaging on a clinical 1.5T platform

“…Angiotensin II is a naturally-occurring hormone with a complex role within the renal renin-angiotensin system (RAS) [ 29 ]. The hormone has a direct effect on the proximal tubules to increase Na + reabsorption, and has a convoluted and variable effect on glomerular filtration and renal blood flow.…”