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Clinical hypertension (HT) is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (Ang II)-induced HT response. The present study aimed to elucidate the effects of IL-1Ra and anti-IL-1β antibody (01BSUR) on Ang II-induced renal injury. To determine the contribution of IL-1Ra to Ang II-induced renal inflammation, male wildtype (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with Ang II (1000 ng/kg/min) using subcutaneous osmotic pump for 14 days. We checked renal function, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197 ± 5 vs 169 ± 9 mmHg, P

Brain renin–angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6–8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (

Insulin-regulated aminopeptidase (IRAP), an enzyme that cleaves vasoactive peptides including oxytocin and vasopressin, is suggested to play a role in pregnancy and the onset of preeclampsia. Our aim was to examine the contribution of IRAP to arterial pressure regulation and placental development during pregnancy in mice. Mean arterial pressure and heart rate were measured via radiotelemetry in 12-week-old female wild-type and IRAP knockout mice. Females were time-mated with males of the same genotype. Placentae were collected at embryonic day 18.5 for histological analysis. Basal heart rate was ∼40 bpm lower in IRAP knockout females compared with wild-type females. The increase in heart rate across gestation was greater in IRAP knockout females than wild-type females. Neither basal nor gestational mean arterial pressure was different between wildtype and IRAP knockout females. Urine output and water intake of IRAP knockout mice were ∼45% less than wild-type mice at late gestation. IRAP deficiency had no effect on fetal weight. Morphological assessment of placentae revealed that IRAP deficiency was associated with reduced labyrinth surface area and accumulation of glycogen in the junctional zone. Our data demonstrate that IRAP deficiency alters maternal fluid handling and impairs placental labyrinth expansion at late gestation, indicating that IRAP contributes to the normal adaptions to pregnancy.

Kir5.1 (encoded by the Kcnj16 gene) is an inwardly rectifying K+ (Kir) channel highly expressed in the aldosterone-sensitive distal nephron of the kidney, where it forms a functional channel with Kir4.1. Kir4.1/Kir5.1 channels are responsible for setting the transepithelial voltage in the distal nephron and collecting ducts and are thereby major determinants of fluid and electrolyte distribution. These channels contribute to renal blood pressure control and have been implicated in salt-sensitive hypertension. However, mechanisms pertaining to the impact of K ir4.1/Kir5.1-mediated K+ transport on the renin–angiotensin–aldosterone system (RAAS) remain unclear. Herein, we utilized a knockout of Kcnj16 in the Dahl salt-sensitive rat (SSKcnj16-/-) to investigate the relationship between Kir5.1 and RAAS balance and function in the sensitivity of blood pressure to the dietary Na+/K+ ratio. The knockout of Kcnj16 caused substantial elevations in plasma RAAS hormones (aldosterone and angiotensin peptides) and altered the RAAS response to changing the dietary Na+/K+ ratio. Blocking aldosterone with spironolactone caused rapid mortality in SSKcnj16-/- rats. Supplementation of the diet with high K+ was protective against mortality resulting from aldosterone-mediated mechanisms. Captopril and losartan treatment had no effect on the survival of SSKcnj16-/- rats. However, neither of these drugs prevented mortality of SSKcnj16-/- rats when switched to high Na+ diet. These studies revealed that the knockout of Kcnj16 markedly altered RAAS regulation and function, suggesting Kir5.1 as a key regulator of the RAAS, particularly when exposed to changes in dietary sodium and potassium content.

Hypertension is the primary risk factor for cardiovascular disease that constitutes a serious worldwide health concern and a significant healthcare burden. As the majority of hypertension has an unknown etiology, considerable research efforts in both experimental models and human cohorts has focused on the premise that alterations in the fetal and perinatal environment are key factors in the development of hypertension in children and adults. The exact mechanisms of how fetal programming events increase the risk of hypertension and cardiovascular disease are not fully elaborated; however, the focus on alterations in the biochemical components and functional aspects of the renin–angiotensin (Ang) system (RAS) has predominated, particularly activation of the Ang-converting enzyme (ACE)-Ang II-Ang type 1 receptor (AT1R) axis. The emerging view of alternative pathways within the RAS that may functionally antagonize the Ang II axis raise the possibility that programming events also target the non-classical components of the RAS as an additional mechanism contributing to the development and progression of hypertension. In the current review, we evaluate the potential role of the ACE2-Ang-(1-7)-Mas receptor (MasR) axis of the RAS in fetal programming events and cardiovascular and renal dysfunction. Specifically, the review examines the impact of fetal programming on the Ang-(1-7) axis within the circulation, kidney, and brain such that the loss of Ang-(1-7) expression or tone, contributes to the chronic dysregulation of blood pressure (BP) and cardiometabolic disease in the offspring, as well as the influence of sex on potential programming of this pathway.

TRV027 is a biased agonist for the Angiotensin (Ang)-II type 1 receptor (AT1R), able to recruit β-arrestin 2 independently of G-proteins activation. β-arrestin activation in the central nervous system (CNS) was suggested to oppose the effects of Ang-II. The present study evaluates the effect of central infusion of TRV027 on arterial pressure (AP), autonomic function, baroreflex sensitivity (BRS), and peripheral vascular reactivity. Spontaneously hypertensive (SH) and Wistar Kyoto (WKY) rats were treated with TRV027 for 14 days (20 ng/h) delivered to the lateral ventricle via osmotic minipumps. Mechanistic studies were performed in HEK293T cells co-transfected with AT1R and Ang converting enzyme type 2 (ACE2) treated with TRV027 (100 nM) or Ang-II (100 nM). TRV027 infusion in SH rats (SHR) reduced AP (~20 mmHg, P

Background: Hypertension is prevalent in chronic kidney disease (CKD). Studies suggest that reduction in dietary salt intake reduces blood pressure (BP). We studied relationships between salt intake, BP and renin–angiotensin system regulation in order to establish if it is disordered in CKD. Methods: Mechanistic crossover study of CKD patients versus non-CKD controls. Participants underwent modified saline suppression test prior to randomization to either low or high salt diet for 5 days and then crossed over to the alternate diet. Angiotensin-II stimulation testing was performed in both salt states. BP, urea and electrolytes, and plasma aldosterone concentration (PAC) were measured. Results: Twenty-seven subjects were recruited (12 CKD, 15 control). There was no difference in age and baseline BP between the groups. Following administration of intravenous saline, systolic BP increased in CKD but not controls (131 ± 16 to 139 ± 14 mmHg, P=0.016 vs 125 ± 20 to 128 ± 22 mmHg, P=0.38). Median PAC reduced from 184 (124,340) to 95 (80,167) pmol in controls (P=0.003), but failed to suppress in CKD (230 (137,334) to 222 (147,326) pmol (P=0.17)). Following dietary salt modification, there was no change in BP in either group. Median PAC was lower following high salt compared with low salt diet in CKD and controls. There was a comparable increase in systolic BP in response to angiotensin-II in both groups. Discussion: We demonstrate dysregulation of aldosterone in CKD in response to salt loading with intravenous saline, but not to dietary salt modification.