Posts Tagged: renin

Hypertension: Renin–Angiotensin–Aldosterone System Alterations

Hypertension: Renin–Angiotensin–Aldosterone System Alterations

Luuk te Riet, Joep H.M. van Esch, Anton J.M. Roks, Anton H. van den Meiracker, A.H. Jan Danser

Circulating versus tissue renin–angiotensin (Ang) system. Circulating renin is kidney-derived, and circulating angiotensinogen originates in the liver. Angiotensin-converting enzyme (ACE) is located on endothelial cells. Ang II generated in the circulation will diffuse to tissues to bind to its main receptor (the Ang II type 1 receptor, AT1R) to exert effects. In addition, circulating renin and angiotensinogen might also diffuse to tissue sites (eg, the interstitial space) and generate, with the help of tissue ACE, Ang II locally. In a limited number of tissues, renin’s precursor prorenin is produced locally. To what degree such prorenin, for example, following its conversion to renin, contributes to local angiotensin production remains unknown. Although local production has also been claimed for angiotensinogen, in particular in the kidney, current evidence does not support a functional role for kidney-derived angiotensinogen because the renal Ang II levels in renal angiotensinogen knockout (KO) mice are identical to those in wild-type mice.11 Locally generated Ang II rapidly binds to AT1 and AT2 receptors, the former being followed by internalization. This explains the intracellular presence of Ang II, as well as the high tissue levels of Ang II in high AT1 receptor-density organs like the adrenal (Illustrated Credit: Ben Smith). [Powerpoint File]

Hypertension: Renin–Angiotensin–Aldosterone System Alterations

Hypertension: Renin–Angiotensin–Aldosterone System Alterations

Luuk te Riet, Joep H.M. van Esch, Anton J.M. Roks, Anton H. van den Meiracker, A.H. Jan Danser

Mutations in ion channels (encoded by the genes KCNJ5, ATP1A1, CACNA1D, and ATP2B3) of the adrenal glomerulosa cell that have recently been linked to excessive aldosterone production. Normally, AT1 receptor activation induces depolarization as a result of inactivation of the potassium channel Kir3.4 and Na+,K+-ATPase. Such depolarization triggers Ca2+-influx via voltage-gated Ca2+ channels (Cav1.3), and the resultant rise in intracellular Ca2+ activates the aldosterone synthase gene CYP11B2. Ca2+-ATPase subsequently removes Ca2+ from the cell. KCNJ5 mutations affect the selectivity of the Kir3.4, now also allowing Na+ conductance. Similarly, mutations in ATP1A1 result in loss of pump activity and strongly reduced affinity for potassium, thereby increasing intracellular Na+. Increased Na+ levels cause depolarization, even in the absence of AT1 receptor stimulation. Mutations in CACNA1D facilitate Ca2+ influx, whereas mutations in ATP2B3 hamper its removal from the cell, thus both elevating intracellular Ca2+. This activates CYP11B2 transcription. [Powerpoint File]

Hypertension: Renin–Angiotensin–Aldosterone System Alterations

Hypertension: Renin–Angiotensin–Aldosterone System Alterations

Luuk te Riet, Joep H.M. van Esch, Anton J.M. Roks, Anton H. van den Meiracker, A.H. Jan Danser

Effects of angiotensin (Ang) II, via its Ang II type 1 and 2 (AT1 and AT2) receptors (AT1R, AT2R) on vascular remodeling and constriction/vasodilation. Transforming growth factor-β (TGF-β) signaling by the TGF-β receptor (via the Smad2/3 pathway) and mitogen-activated protein kinase (MAPK) activation after AT1 receptor stimulation jointly regulate the transcription of target genes (eg, matrix metalloproteinase, MMP; plasminogen-activator inhibitor-1, PAI-1; connective tissue growth factor, CTGF) that result in proliferation, extracellular matrix production/fibrosis, differentiation, and inflammation. AT1 receptor stimulation additionally upregulates NAD(P)H oxidase (NOX), thereby increasing reactive oxygen species (ROS) formation, which also regulates the transcription of the above-mentioned target genes. AT2 receptor stimulation inhibits this pathway by blocking MAPK. AT2 receptors also induce vasorelaxation by activating NO synthase (NOS). This may counteract the constrictor effects of AT1 receptor stimulation (mediated by the inositol trisphosphate [IP3]-Ca2+ and diacylglycerol [DAG]-protein kinase C [PKC] pathways). Under pathological condition, ROS uncouple NOS, thereby diminishing NO production and potentially facilitating ROS formation by NOS. [Powerpoint File]