The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable o...

https://www.physiology.org/doi/pdf/10.1152/physrev.00011.2009

Physiology of Kidney Renin

▪ Abstract Angiotensin receptors are present in a number of organs and systems including heart, kidney, gonad, and placenta; pituitary and adrenal glands; the peripheral vessels, and the central ne...

Biological functions of angiotensin and its receptors

Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure–regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.

https://pharmrev.aspetjournals.org/content/pharmrev/71/4/539.full.pdf

Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure.

Although renin and angiotensinogen are known to be subject to feedback regulation, the effects of angiotensin II (Ang II) on the regulation of angiotensin converting enzyme (ACE) gene expression and enzymatic activity have not yet been studied. Therefore, the effects of exogenous Ang II infusion and ACE inhibition on ACE mRNA expression were examined. Ang II was infused intravenously in male Sprague-Dawley rats for 3 days at 100 (low dose), 300 (medium dose), or 1,000 (high dose) ng/kg per minute (n = 8 for each group). Compared with control (vehicle infusion, n = 8), Ang II infusion increased plasma Ang II concentration (62, 101, 126 [p < 0.05], and 187 [p < 0.05] fmol/ml) and mean arterial blood pressure (106, 119 [p < 0.05], 134 [p < 0.05], and 125 mm Hg for control, low, medium, and high doses, respectively). Ang II infusion decreased ACE mRNA levels in the lung (57%, 52%, and 51%; p < 0.05 for each) and testis (49%, 63%, and 53% of control for low, medium, and high doses, respectively; p < 0.05 for each), two major sites of ACE synthesis. There was, albeit less pronounced, a parallel decrease in pulmonary ACE activity (4.38, 3.92, 3.07 [p < 0.05], and 3.48 [p < 0.05] nM/mg per minute for control, medium, and high doses, respectively). In contrast, serum (54, 50, 48, and 38 [p < 0.05] nM/ml per minute) and testicular (2.63, 2.08 [p < 0.05], 2.24, and 2.18 nM/mg per minute for control, low, medium, and high doses, respectively) ACE activities displayed only minimal change in animals infused with Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)

Feedback regulation of angiotensin converting enzyme activity and mRNA levels by angiotensin II.

The prevalence of vitamin D insufficiency, defined by a 25-hydroxyvitamin D (25[OH]D) level <30 ng/mL, in the United States was 77% in 2004.1 Although the use of vitamin D supplementation may be increasing since 2004, it is likely that the majority of US citizens continue to have inadequate vitamin D status.2 Observational studies suggest that low 25(OH)D levels are associated with a higher risk of hypertension. However, findings from randomized trials of vitamin D supplementation to lower blood pressure are inconsistent, possibly stemming from variability in study population, sample size, vitamin D dose, and duration. If vitamin D supplementation lowers blood pressure, its widespread use could have major public health benefits. In this review, we summarize the existing literature dealing with the vitamin D-hypertension link, including mechanistic studies, observational data, and clinical trials; we place special emphasis on recent findings.

Biological mechanisms relating vitamin D with hypertension have been proposed for >25 years. Vitamin D has been implicated in the proximal regulation of the renin-angiotensin system (RAS) and in interacting with the RAS to determine the intracellular calcium milieu in vascular smooth muscle.

### Vitamin D and the RAS

Dietary sodium and increased activity of the RAS are known to contribute to hypertension; salt restriction and inhibition of RAS activity reduce blood pressure.3–5 Li et al6 provided convincing support for vitamin D as a proximal inhibitor of the RAS when they described a phenotype of excess plasma renin activity and hypertension in mice lacking the vitamin D receptor, which normalized after treatment with RAS antagonists. These vitamin D receptor–null mice also displayed an increased susceptibility to obstructive renal injury that could be prevented with RAS antagonism.7 Mice with deficient 1α-hydroxylase activity were also found to have increased plasma renin activity and hypertension, and this unfavorable phenotype could be reversed with 1,25-dihydroxyvitamin …

Vitamin D and Hypertension: Current Evidence and Future Directions

The effects of removing external calcium and inhibiting entry of calcium into the cell by treatment with D-600 on renin release from renal cortical slices of male Sprague-Dawley rats were examined. Baseline renin release, angiotensin II (AII)-induced inhibition, and isoproterenol-induced stimulation of renin release were studied. Removal of external calcium by chelation with 5 mM EGTA inhibited basal renin release while treatment with 1 mM EGTA stimulated basal renin release slightly. Incubation of slices with zero calcium medium containing 1 mM EGTA had no effect on isoproterenol-induced stimulation of renin release. In contrast, similar treatment reduced the inhibitory effect of AII from 58.7% of baseline to 85.3% (p less than 0.001). Similarly, blockage of calcium entry into cells with D-600 had no effect on isoproterenol-induced stimulation of renin release but abolished AII-induced inhibition. Replacement of sodium in the bathing medium with choline had no effect on baseline renin release or on AII-induced inhibition of renin release, ruling out the possibility that D-600 altered renin release via an effect on sodium influx. Taken together, the data strongly suggest that AII-induced inhibition of renin release is partially dependent on the presence of external calcium but that isoproterenol-induced stimulation of renin release is not.

The role of calcium in the control of renin release.

The mechanism and structural basis of the inhibition of renin release by angiotensin II (AII) were studied in rat kidney slices. Renin release was inhibited by AII and the (2–8), (3–8), (4–8), and (5–8) peptides of AII (5 X 10(-5) M). These constituent peptides of AII which share a common carboxyl terminus inhibited renin release with a sharp decrease in potency when the amino-terminal amino acid was removed. Saralasin attenuated the inhibition of renin release induced by equimolar concentrations of AII. Dose-response curves for AII and the (2–8) peptide [angiotensin III (AIII)] indicate that AII is a more potent inhibitor of renin release than is AIII. Depletion of renal norepinephrine by reserpine (10 mg/kg, i.p.) or pretreatment of slices with papaverine (1 X 10(-4) M) did not block the action of AII. The data give evidence for a direct action of AII on the juxtaglomerular cells independent of an interaction with either the sympathetic nervous system or the arteriolar baroreceptor and suggest that the ...

A. J. Naftilan

Papers

The role of calcium in the control of renin release.

Inhibition of renin release from rat kidney slices by the angiotensins