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Background: Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI 2 ). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI 2 during angiogenesis inhibition., Methods: Male WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI 2 analogue (iloprost, 100 μg/kg/day) for 8 days (n = 8-9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography., Results: SU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P < 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI 2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P < 0.001), but not circulating PGI 2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost., Conclusion: Selective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition with sunitinib, which most likely acts independently of PGI 2 . To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Gut dysfunction has emerged as a contributor to hypertension, the leading risk factor for disease globally, including stroke, heart failure, and kidney disease. This is underpinned by breakdown of the homeostatic relationship connecting intestinal epithelial function, the microbiota and immune responses. Antihypertensive medications have been shown to reverse intestinal dysfunction and gut dysbiosis. However, the mechanisms underlying this restoration of gut structure and function remain largely unknown. In this review, we examine current knowledge supporting a role for impaired intestinal epithelial permeability in hypertension, focusing on electrolyte movement, the renin-angiotensin-aldosterone system, and the restorative effects of orally administered antihypertensive medications and antibiotics. Further work is required to determine if the association between intestinal dysfunction and hypertension is causal. This is a rapidly evolving field, with intestinal dysfunction and dysbiosis representing an area that may be exploited to improve treatment of hypertension and cardiovascular disease., Competing Interests: Disclosures D. Lyras has received funding from MSD (Merck Sharpe and Dohme; Grant number: IIS57443) to investigate bezlotoxumab. MSD had no input into this review. The other authors report no conflicts.

Background: Vascular endothelial growth factor inhibitors (VEGFIs) are effective anticancer agents which often induce hypertension. VEGFI-induced hypertension is sodium-sensitive in animal studies. Therefore, the efficacy of dietary sodium restriction (DSR) to prevent VEGFI-induced hypertension in cancer patients was studied., Methods: Cancer patients with VEGFI-induced hypertension (day mean >135/85 mmHg or a rise in systolic and/or diastolic BP ≥ 20 mmHg) were treated with DSR (aiming at <4 g salt/day). The primary endpoint was the difference in daytime mean arterial blood pressure (MAP) increase between the treatment cycle with and without DSR., Results: During the first VEGFI treatment cycle without DSR, mean daytime MAP increased from 95 to 110 mmHg. During the subsequent treatment cycle with DSR, mean daytime MAP increased from 94 to 102 mmHg. Therefore, DSR attenuated the increase in mean daytime MAP by 7 mmHg (95% CI 1.3-12.0, P = 0.009). DSR prevented the rise in the endothelin-1/renin ratio that normally accompanies VEGFI-induced hypertension (P = 0.020) and prevented the onset of proteinuria: 0.15 (0.10-0.25) g/24 h with DSR versus 0.19 (0.11-0.32) g/24 h without DSR; P = 0.005., Discussion: DSR significantly attenuated VEGFI induced BP rise and proteinuria and thus is an effective non-pharmacological intervention., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Cardiovascular disease remains the leading cause of death worldwide. Cardiovascular research has therefore never been more crucial. Cardiovascular researchers must be provided with a research environment that enables them to perform at their highest level, maximizing their opportunities to work effectively with key stakeholders to address this global issue. At present, cardiovascular researchers face a range of challenges and barriers, including a decline in funding, job insecurity and a lack of diversity at senior leadership levels. Indeed, many cardiovascular researchers, particularly women, have considered leaving the sector, highlighting a crucial need to develop strategies to support and retain researchers working in the cardiovascular field. In this Roadmap article, we present solutions to problems relevant to cardiovascular researchers worldwide that are broadly classified across three key areas: capacity building, research funding and fostering diversity and equity. This Roadmap provides opportunities for research institutions, as well as governments and funding bodies, to implement changes from policy to practice, to address the most important factors restricting the career progression of cardiovascular researchers., (© 2022. Springer Nature Limited.)

Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.

Background A single dose of small interfering RNA (siRNA) targeting liver angiotensinogen eliminates hepatic angiotensinogen and lowers blood pressure. Angiotensinogen elimination raises concerns for clinical application because an angiotensin rise is needed to maintain perfusion pressure during hypovolemia. Here, we investigated whether conventional vasopressors can raise arterial pressure after angiotensinogen depletion. Methods and Results Spontaneously hypertensive rats on a low-salt diet were treated with siRNA (10 mg/kg fortnightly) for 4 weeks, supplemented during the final 2 weeks with fludrocortisone (6 mg/kg per day), the α-adrenergic agonist midodrine (4 mg/kg per day), or a high-salt diet (all groups n=6-7). Pressor responsiveness to angiotensin II and norepinephrine was assessed before and after siRNA administration. Blood pressure was measured via radiotelemetry. Depletion of liver angiotensinogen by siRNA lowered plasma angiotensinogen concentrations by 99.2±0.1% and mean arterial pressure by 19 mm Hg. siRNA-mediated blood pressure lowering was rapidly reversed by intravenous angiotensin II or norepinephrine, or gradually reversed by fludrocortisone or high salt intake. Midodrine had no effect. Unexpectedly, fludrocortisone partially restored plasma angiotensinogen concentrations in siRNA-treated rats, and nearly abolished plasma renin concentrations. To investigate whether this angiotensinogen originated from nonhepatic sources, fludrocortisone was administered to mice lacking hepatic angiotensinogen. Fludrocortisone did not increase angiotensinogen in these mice, implying that the rise in angiotensinogen in the siRNA-treated rats must have depended on the liver, most likely reflecting diminished cleavage by renin. Conclusions Intact pressor responsiveness to conventional vasopressors provides pharmacological means to regulate the blood pressure-lowering effect of angiotensinogen siRNA and may support future therapeutic implementation of siRNA.

The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT 1 ) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT 1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation., (Copyright © 2022 by The Author(s).)

Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors., (© 2022 The Author(s).)

Previous studies showed that postmenopausal women are more likely to have poorly controlled hypertension than men of the same age. Whether this is caused by inadequate treatment or poor response to antihypertensive agents remains unknown. The aim of this study is to analyze treatment response to the most potent renin angiotensin aldosterone system (RAAS) inhibitor perindopril in different age categories in women and men. Individual patient data were used from the combined European Trial on Reduction of Cardiac Events With Perindopril (EUROPA), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trials, which include patients with vascular disease (n = 29,463). We studied the relative and absolute changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during a 4-week run-in phase in which all patients were treated with the perindopril-based treatment in different age categories. In total, 8366 women and 21,097 men were included in the analysis. Women greater than 65 years of age showed a significantly smaller blood pressure reduction after perindopril treatment (2.8 mmHg [95% confidence interval {CI} = 0.1-5.5] less reduction compared to women ≤45 years, p = 0.039). In men, the SBP reduction after perindopril in patients greater than 55-65 and greater than 65 years was lower compared to the age category less than or equal to 45 years (adjusted mean difference >55-65: 2.8 mmHg [95% CI = 1.8-3.7], p < 0.001, >65: 3.7 mmHg [95% CI = 2.7-4.7], p < 0.001). A trend of less blood pressure reduction was seen with ageing in both men and women (p < 0.001). To conclude, we observed that in both women and men the perindopril leads to less SBP reduction with increasing age, whereas the DBP reduction increases with age. More research is needed to determine whether it would be beneficial to use age-adjusted perindopril dosages., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: The antifibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (AT 2 R) in male models of disease. Whether RLX has therapeutic effects, which are also mediated via AT 2 R, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection via an AT 2 R-dependent mechanism in adult and aged female stroke-prone spontaneously hypertensive rats (SHRSPs)., Methods: In 6-month-old (6MO) and 15-month-old ([15MO]; reproductively senescent) female SHRSP, systolic BP (SBP), GFR, and proteinuria were measured before and after 4 weeks of treatment with vehicle (Veh), RLX (0.5 mg/kg per day s.c.), or RLX+PD123319 (AT 2 R antagonist; 3 mg/kg per day s.c.). Aortic endothelium-dependent relaxation and fibrosis of the kidney, heart, and aorta were assessed., Results: In 6MO SHRSP, RLX significantly enhanced GFR by approximately 25% ( P =0.001) and reduced cardiac fibrosis ( P =0.01) as compared with vehicle-treated counterparts. These effects were abolished or blunted by PD123319 coadministration. In 15MO females, RLX reduced interstitial renal ( P =0.02) and aortic ( P =0.003) fibrosis and lowered SBP (13±3 mm Hg; P =0.04) relative to controls. These effects were also blocked by PD123319 cotreatment (all P =0.05 versus RLX treatment alone). RLX also markedly improved vascular function by approximately 40% ( P <0.001) in 15MO SHRSP, but this was not modulated by PD123319 cotreatment., Conclusions: The antifibrotic and organ-protective effects of RLX, when administered to a severe model of hypertension, conferred cardiorenal protection in adult and reproductively senescent female rats to a great extent via an AT 2 R-mediated mechanism., Competing Interests: K.M. Denton reports scientific advisor or membership with American Journal of Physiology–Renal Physiology, Experimental Physiology, Frontiers of Science–Integrative Physiology, Hypertension, and Journal of Hypertension. C.S. Samuel reports scientific advisor or membership as a senior editor of Clinical and Experimental Pharmacology and Physiology, an associate editor of Frontiers in Pharmacology–Cardiovascular and Smooth Muscle Pharmacology, a subject editor of Nephrology, and a scientific advisory board member of Relaxera Pharmazeutische Gesellschaft GmbH & Co. KG, Bensheim, Germany. All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

In the past two decades, treatment outcomes for a wide range of malignancies have improved remarkably due to the development of novel anti-cancer therapies, including vascular endothelial growth factor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs). Despite their unprecedented anti-tumour effects, it is becoming increasingly clear that both types of agents are associated with specific cardiovascular toxicity, including hypertension, congestive heart failure, myocarditis and acceleration of atherosclerosis. Currently, VEGFI and ICI combination therapy is recommended for the treatment of advanced renal cell carcinoma (RCC) and has shown promising treatment efficacy in other tumour types as well. Consequently, VEGFI and ICI combination therapy will most likely become an important therapeutic strategy for various malignancies. However, this combinatory approach is expected to be accompanied by a substantial increase in cardiovascular risk, as both types of agents could act synergistically to induce cardiovascular sequelae. Therefore, a comprehensive baseline assessment and adequate monitoring by specialised cardio-oncology teams is essential in case these agents are used in combination, particularly in high-risk patients. This review summarises the mechanisms of action and treatment indications for currently registered VEGFIs and ICIs, and discusses their main vascular and cardiac toxicity. Subsequently, we provide the biological rationales for the observed promising synergistic anti-tumour effects of combined VEGFI/ICI administration. Lastly, we speculate on the increased risk for cardiovascular toxicity in case these agents are used in combination and its implications and future directions for the clinical situation., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

[Figure: see text].

The endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ET A R blockade, but not dual ET A/B R blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.

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 (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97 ± 0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

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., (© 2020 The Author(s).)

Background: Cardiovascular disease is the leading cause of death in Australia. Investment in research solutions has been demonstrated to yield health and a 9.8-fold return economic benefit. The sector, however, is severely challenged with success rates of traditional peer-reviewed funding in decline. Here, we aimed to understand the perceived challenges faced by the cardiovascular workforce in Australia prior to the COVID-19 pandemic., Methods: We used an online survey distributed across Australian cardiovascular societies/councils, universities and research institutes over a period of 6 months during 2019, with 548 completed responses. Inclusion criteria included being an Australian resident or an Australian citizen who lived overseas, and a current or past student or employee in the field of cardiovascular research., Results: The mean age of respondents was 42±13 years, 47% were male, 85% had a full-time position, and 40% were a group leader or laboratory head. Twenty-three per cent (23%) had permanent employment, and 82% of full-time workers regularly worked >40 hours/week. Sixty-eight per cent (68%) said they had previously considered leaving the cardiovascular research sector. If their position could not be funded in the next few years, a staggering 91% of respondents would leave the sector. Compared to PhD- and age-matched men, women were less likely to be a laboratory head and to feel they had a long-term career path as a cardiovascular researcher, while more women were unsure about future employment and had considered leaving the sector (all p<0.05). Greater job security (76%) and government and philanthropic investment in cardiovascular research (72%) were highlighted by responders as the main changes to current practices that would encourage them to stay., Conclusion: Strategic solutions, such as diversification of career pathways and funding sources, and moving from a competitive to a collaborative culture, need to be a priority to decrease reliance on government funding and allow cardiovascular researchers to thrive., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Chronic kidney disease (CKD) causes salt-sensitive hypertension that is often resistant to treatment and contributes to the progression of kidney injury and cardiovascular disease. A better understanding of the mechanisms contributing to salt-sensitive hypertension in CKD is essential to improve these outcomes. This review critically explores these mechanisms by focusing on how CKD affects distal nephron Na + reabsorption. CKD causes glomerulotubular imbalance with reduced proximal Na + reabsorption and increased distal Na + delivery and reabsorption. Aldosterone secretion further contributes to distal Na + reabsorption in CKD and is not only mediated by renin and K + but also by metabolic acidosis, endothelin-1, and vasopressin. CKD also activates the intrarenal renin-angiotensin system, generating intratubular angiotensin II to promote distal Na + reabsorption. High dietary Na + intake in CKD contributes to Na + retention by aldosterone-independent activation of the mineralocorticoid receptor mediated through Rac1. High dietary Na + also produces an inflammatory response mediated by T helper 17 cells and cytokines increasing distal Na + transport. CKD is often accompanied by proteinuria, which contains plasmin capable of activating the epithelial Na + channel. Thus, CKD causes both local and systemic changes that together promote distal nephron Na + reabsorption and salt-sensitive hypertension. Future studies should address remaining knowledge gaps, including the relative contribution of each mechanism, the influence of sex, differences between stages and etiologies of CKD, and the clinical relevance of experimentally identified mechanisms. Several pathways offer opportunities for intervention, including with dietary Na + reduction, distal diuretics, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and K + or H + binders.

Aims: Although effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro- or anti-hypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria., Methods and Results: Male Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of ∼25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib- than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan., Conclusions: Our results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Since the 1970s, we have known that aspirin can reduce the risk of pre-eclampsia. However, the underlying mechanisms explaining this risk reduction are poorly understood. Both cyclooxygenase (COX)-1- and COX-2-dependent effects might be involved. As a consequence of this knowledge hiatus, the optimal dose and timing of initiation of aspirin therapy are not clear. Here, we review how (COX-1 versus COX-2 inhibition) and when (prevention versus treatment) aspirin therapy may interfere with the mechanisms implicated in the pathogenesis of pre-eclampsia. The available evidence suggests that both COX-1- and COX-2-dependent effects play important roles in the early stage of aberrant placental development and in the next phase leading to the clinical syndrome of pre-eclampsia. Collectively, these data suggest that high-dose (dual COX inhibition) aspirin may be superior to standard low-dose (selective COX-1 inhibition) aspirin for the prevention and also treatment of pre-eclampsia. Therefore, we conclude that more functional and biochemical tests are needed to unravel the contribution of prostanoids in the mechanisms implicated in the pathogenesis of pre-eclampsia and the potential of dual COX and/or selective COX-2 inhibition for the prevention and treatment of pre-eclampsia. This information is vital if we are to deduce the suitability, optimal timing and dose of aspirin and/or a specific COX-2 inhibitor (most likely using modified forms that do not cross the placenta) that can then be tested in a randomized, controlled trial instead of the current practice of empirical dosing regimens., (© 2019 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

: The New Investigators Committee (NIC) of the International Society of Hypertension (ISH) is a dynamic group of junior doctors and scientists, actively involved in various society activities. This report highlights the events (scientific meetings and summer schools) and activities (social media, mentorship and networking) during 2019 including May Measurement Month and collaborative efforts with the ISH Women in Hypertension Research Committee (WiHRC). The ISH NIC is proud to sponsor awards for outstanding work by junior and emerging researchers at hypertension conferences and also provides opportunities to showcase their work on our social media features such as 'Our Fellows Work' and the New Investigator Spotlight of the month. In 2020, the ISH NIC aims to promote women in leadership roles and to foster strong collaborations with and between society committees and other scientific organizations.

Background: Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated via its cognate G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1), has emerged as a potential agent to treat fibrosis. Studies have shown that serelaxin requires the angiotensin II (AngII) type 2 receptor (AT 2 R) to ameliorate renal fibrogenesis in vitro and in vivo . Whether its antifibrotic actions are affected by modulation of the AngII type 1 receptor (AT 1 R), which is expressed on myofibroblasts along with RXFP1 and AT 2 R, is unknown., Methods: We examined the signal transduction mechanisms of serelaxin when applied to primary rat renal and human cardiac myofibroblasts in vitro , and in three models of renal- or cardiomyopathy-induced fibrosis in vivo ., Results: The AT 1 R blockers irbesartan and candesartan abrogated antifibrotic signal transduction of serelaxin via RXFP1 in vitro and in vivo . Candesartan also ameliorated serelaxin's antifibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that candesartan's inhibitory effects were not confined to the kidney. We also demonstrated in a transfected cell system that serelaxin did not directly bind to AT 1 Rs but that constitutive AT 1 R-RXFP1 interactions could form. To potentially explain these findings, we also demonstrated that renal and cardiac myofibroblasts expressed all three receptors and that antagonists acting at each receptor directly or allosterically blocked the antifibrotic effects of either serelaxin or an AT 2 R agonist (compound 21)., Conclusions: These findings have significant implications for the concomitant use of RXFP1 or AT 2 R agonists with AT 1 R blockers, and suggest that functional interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression., (Copyright © 2019 by the American Society of Nephrology.)

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and body fluid homeostasis and is a mainstay for the treatment of cardiovascular and renal diseases. Angiotensin II and aldosterone are the two most powerful biologically active products of the RAAS, inducing all of the classical actions of the RAAS including vasoconstriction, sodium retention, tissue remodeling and pro-inflammatory and pro-fibrotic effects. In recent years, new components of the RAAS have been discovered beyond the classical pathway that have led to the identification of depressor or so-called protective RAAS pathways and the development of novel therapies targeting this system. Moreover, dual inhibitors which block the RAAS and other systems involved in the regulation of blood pressure or targeting upstream of angiotensin II by selectively deleting liver-derived angiotensinogen, the precursor to all angiotensins, may provide superior treatment for cardiovascular and renal diseases and revolutionize RAAS-targeting therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity., Methods: Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified., Findings: Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ± 0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS were comparable in both groups, while PDE1 levels were lower in PE., Interpretation: The absence of sildenafil-induced NO potentiation in arteries of PE placentas, combined with the non-PDE-mediated effects of sildenafil and the lack of PDE5 upregulation in PE, argue against sildenafil as the preferred drug of use in PE. Moreover, increased placental transfer of sildenafil in PE might underlie the neonatal morbidity in the STRIDER trial. FUND: This study was funded by an mRACE Erasmus MC grant., (Copyright © 2019. Published by Elsevier B.V.)

Preeclampsia (PE) is a pregnancy complication, featuring elevated blood pressure and proteinuria, with no appropriate treatment. Activation of the endothelin system has emerged as an important pathway in PE pathophysiology based on experimental PE models where endothelin receptor antagonists (ERAs) prevented or attenuated hypertension and proteinuria. Hence, ERAs have been suggested as potential therapy for PE. However, developmental toxicity studies in animals have shown severe teratogenic effects of ERAs, particularly craniofacial malformations. Nonetheless, sporadic cases of pregnancy in women using ERAs to treat pulmonary hypertension have been described. In this review we give an overview of cases describing ERA use in pregnancy and critically address their possible teratogenic effects. A systematic search in literature yielded 18 articles describing 39 cases with ERA exposure during human pregnancy. In most cases there was only exposure in the first trimester, but exposure later or throughout pregnancy was reported in five cases. Elective termination of pregnancy was performed in 12 pregnancies (31%), two ended in a spontaneous miscarriage (5%) and no fetal congenital abnormalities have been described in the remaining cases. These preliminary findings support the idea that ERA treatment for severe, early onset PE might be an option if applied later in pregnancy, when organogenesis is completed to avoid teratogenic risks. However, third trimester toxicology studies are warranted to evaluate drug safety. Subsequently, it remains to be established whether ERA treatment is effective for alleviating maternal symptoms, as demonstrated in preclinical PE models, allowing pregnancy prolongation without leading to adverse neonatal outcomes., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen ( Agt) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (-68±4 mm Hg), followed by captopril+valsartan (-54±4 mm Hg), captopril (-23±2 mm Hg), siRNA (-14±2 mm Hg), and valsartan (-10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K + increased with every treatment, but especially during valsartan+siRNA; no effects on aldosterone were observed. Collectively, these data indicate that Ang II elimination requires >99% suppression of circulating AGT. Maximal blockade of the renin-angiotensin system, achieved by valsartan+siRNA, yielded the greatest reduction in blood pressure and cardiac hypertrophy, whereas AGT lowering alone was as effective as conventional renin-angiotensin system inhibitors. Given its stable and sustained efficacy, lasting weeks, RNA interference may offer a unique approach to improving therapy adherence and treating hypertension.

Since the formation of new blood vessels is essential for tumour growth and metastatic spread, inhibition of angiogenesis by targeting the vascular endothelial growth factor (VEGF) pathway is an effective strategy for various types of cancer, most importantly renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. However, VEGF inhibitors have serious side effects, most importantly hypertension and nephropathy. In case of fulminant hypertension, this may only be handled by lowering the dosage since the blood pressure rise is proportional to the amount of VEGF inhibition. These effects pathophysiologically and clinically resemble the most severe complication of pregnancy, preeclampsia, in which case an insufficient placenta leads to a rise in sFlt-1 levels causing a decrease in VEGF availability. Due to this overlap, studies in preeclampsia may provide important information for VEGF inhibitor-induced toxicity and vice versa. In both VEGF inhibitor-induced toxicity and preeclampsia, endothelin (ET)-1 appears to be a pivotal player. In this review, after briefly summarizing the anticancer effects, we discuss the mechanisms that potentially underlie the unwanted effects of VEGF inhibitors, focusing on ET-1, nitric oxide and oxidative stress, the renin-angiotensin-aldosterone system, and rarefaction. Given the salt sensitivity of this phenomenon, as well as the beneficial effects of aspirin in preeclampsia and cancer, we next provide novel treatment options for VEGF inhibitor-induced toxicity, including salt restriction, ET receptor blockade, and cyclo-oxygenase inhibition, in addition to classical antihypertensive and renoprotective drugs. We conclude with the recommendation of therapeutic drug monitoring to improve patient outcome., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

In a recent issue of Clinical Science, Stanhewicz et al. investigated persistent microvascular dysfunction in women up to 16 months postpartum. The authors found sensitivity to the pressor effects of endothelin-1 (ET-1) was enhanced when compared with women who had a normotensive pregnancy. Importantly, the authors demonstrated that this effect was mediated via the endothelin type B (ET B ) receptors. Therefore, the present study highlights the possibility that alterations in the localization of the ET B receptor contributes to the pathogenesis of pre-eclampsia and future cardiovascular disease (CVD) risk. Currently, there is great interest in the role of the endothelin system in pre-eclampsia. Targetting the endothelin system, potentially by modulating upstream pathways to prevent ET B receptor dysfunction, may improve health outcomes for women and their offspring during pre-eclampsia and later life., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Relaxin is increasingly being recognized as a potent vasodilatory and antifibrotic hormone. Given that relaxin is present in the circulation during the luteal phase of the menstrual cycle and during pregnancy, when arterial pressure is lowest in women, relaxin may contribute to the relative cardiovascular protection observed in premenopausal women as compared with age-matched men and postmenopausal women. In the present study, we investigated the contribution of relaxin to the normal regulation of arterial pressure in adult female and male mice and during pregnancy. Mean arterial pressure (MAP) was measured via radiotelemetry in 14-week-old male and female wild-type (WT; C67BL/6xSv129) and relaxin knockout (KO) mice. Thereafter, female mice were time-mated with a (non-telemetered) male of the same genotype and MAP was measured throughout gestation. Basal MAP was ∼10 mmHg lower in WT females than males ( P <0.05). Relaxin deficiency increased basal MAP in females ( P <0.05 vs WT female), but not males. As expected, MAP decreased during gestation in WT mice. Conversely, in relaxin KO mice, arterial pressure increased during mid and late gestation ( P <0.05 as compared with WT). Moreover, relaxin deficiency impaired gestational weight gain and reduced litter size. This is the first study to (i) demonstrate that relaxin contributes to the sexual dimorphism of arterial pressure in mice and (ii) document the changes in the arterial pressure profile of pregnant relaxin KO mice. Understanding the mechanisms that underlie the regulation of arterial pressure in premenopausal females may uncover new strategies to treat hypertension in women (non-pregnant and pregnant) and men., (© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Zinc is an essential micronutrient in pregnancy and zinc deficiency impairs fetal growth. We used a mouse model of moderate zinc deficiency to investigate the physiological mechanisms by which zinc is important to placental morphogenesis and the maternal blood pressure changes during pregnancy. A 26% reduction in circulating zinc (P = 0.005) was exhibited in mice fed a moderately zinc-deficient diet. Zinc deficiency in pregnancy resulted in an 8% reduction in both near term fetal and placental weights (both P < 0.0001) indicative of disrupted placental development and function. Detailed morphological analysis confirmed changes to the placental labyrinth microstructure. Continuous monitoring of maternal mean arterial pressure (MAP) revealed a late gestation decrease in the zinc-deficient dams. Differential expression of a number of regulatory genes within maternal kidneys supported observations on MAP changes in gestation. Increased MAP late in gestation is required to maintain perfusion of multiple placentas within rodent pregnancies. Decreased MAP within the zinc-deficient dams implies reduced blood flow and nutrient delivery to the placenta. These findings show that adequate zinc status is required for correct placental morphogenesis and appropriate maternal blood pressure adaptations to pregnancy. We conclude that insufficient maternal zinc intake from before and during pregnancy is likely to impact in utero programming of offspring growth and development largely through effects to the placenta and maternal cardiovascular system.

Preeclampsia is a hypertensive disorder of pregnancy. It is associated with abnormal placentation via poor placental invasion of the uterine vasculature by trophoblast cells, leading to poor placental perfusion, oxidative stress, and inflammation, all of which are implicated in its pathogenesis. A dyslipidemia characterized by low plasma levels of high-density lipoproteins (HDL) and elevated triglycerides has been described in preeclampsia. Apolipoprotein A-I (apoA-I), a constituent of HDL is an anti-inflammatory agent. This study investigated whether apoA-I protects against hypertension and adverse placental changes in a proinflammatory cytokine (TNF-α)-induced model of preeclampsia. Further, this study investigated whether apoA-I protects against the inhibitory effect of TNF-α in a human in vitro model of trophoblast invasion. Administration of apoA-I to pregnant mice before infusion with TNF-α resulted in a significant reduction in the cytokine-induced increase in systolic blood pressure. MRI measurement of T 2 relaxation, a parameter that is tissue specific and sensitive to physiological changes within tissues, showed a reversal of TNF-α-induced placental changes. Preincubation of endothelial cells with apoA-I protected against the TNF-α-induced inhibition of HTR-8/SVneo (trophoblast) cell integration into endothelial (UtMVEC) networks. These data suggest that a healthy lipid profile may affect pregnancy outcomes by priming endothelial cells in preparation for trophoblast invasion., (Copyright © 2017 the American Physiological Society.)

Background: Animal models have become valuable experimental tools for understanding the pathophysiology and therapeutic interventions in cardiovascular disease. Yet to date, few studies document the age- and sex-related differences in arterial pressure, circadian rhythm, and renal function in normotensive mice under basal conditions, across the life span. We hypothesized that mice display similar sex- and age-related differences in arterial pressure and renal function to humans., Methods: Mean arterial pressure (MAP) and circadian rhythm of arterial pressure were measured over 3 days via radiotelemetry, in 3- and 5-month-old (adult) and 14- and 18-month-old (aged) FVB/N and in 5-month-old (adult) C57BL/6 male and female normotensive mice. In FVB/N mice, albuminuria from 24-h urine samples as well as body, heart, and kidney weights were measured at each age., Results: Twenty-four-hour MAP was greater in males than females at 3, 5, and 14 months of age. A similar sex difference in arterial pressure was observed in C57BL/6 mice at 5 months of age. In FVB/N mice, 24-h MAP increased with age, with females displaying a greater increase between 3 and 18 months of age than males, such that MAP was no longer different between the sexes at 18 months of age. A circadian pattern was observed in arterial pressure, heart rate, and locomotor activity, with values for each greater during the active (night/dark) than the inactive (day/light) period. The night-day dip in MAP was greater in males and increased with age in both sexes. Albuminuria was greater in males than females, increased with age in both sexes, and rose to a greater level in males than females at 18 months of age., Conclusions: Arterial pressure and albuminuria increase in an age- and sex-specific manner in mice, similar to patterns observed in humans. Thus, mice represent a useful model for studying age and sex differences in the regulation of arterial pressure and renal disease. Understanding the mechanisms that underlie the pathophysiology of cardiovascular disease may lead to new and better-tailored therapies for men and women.

Epidemiological evidence links recurrent dehydration associated with periodic water intake with chronic kidney disease (CKD). However, minimal attention has been paid to the long-term impact of periodic water intake on the progression of CKD and underlying mechanisms involved. Therefore we investigated the chronic effects of recurrent dehydration associated with periodic water restriction on arterial pressure and kidney function and morphology in male spontaneously hypertensive rats (SHR). Arterial pressure increased and glomerular filtration rate decreased in water-restricted SHR. This was observed in association with cyclic changes in urine osmolarity, indicative of recurrent dehydration. Additionally, water-restricted SHR demonstrated greater renal fibrosis and an imbalance in favour of pro-inflammatory cytokine-producing renal T cells compared to their control counterparts. Furthermore, urinary NGAL levels were greater in water-restricted than control SHR. Taken together, our results provide significant evidence that recurrent dehydration associated with chronic periodic drinking hastens the progression of CKD and hypertension, and suggest a potential role for repetitive bouts of acute renal injury driving renal inflammatory processes in this setting. Further studies are required to elucidate the specific pathways that drive the progression of recurrent dehydration-induced kidney disease.

The renin-angiotensin system (RAS) plays a commanding role in the regulation of extracellular fluid homoeostasis. Tigerstadt and Bergman first identified the RAS more than two centuries ago. By the 1980s a voyage of research and discovery into the mechanisms and actions of this system led to the development of drugs that block the RAS, which have become the mainstay for the treatment of cardiovascular and renal disease. In the last 25 years new components of the RAS have come to light, including the angiotensin type 2 receptor (AT2R) and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang(1-7)]/Mas receptor (MasR) axis. These have been shown to counter the classical actions of angiotensin II (AngII) at the predominant angiotensin type 1 receptor (AT1R). Our studies, and those of others, have demonstrated that targeting these depressor RAS pathways may be therapeutically beneficial. It is apparent that the evolution of both the pressor and depressor RAS pathways is distinct throughout life and that the depressor/pressor balance of the RAS vary between the sexes. These temporal patterns of expression suggest that therapies targeting the RAS could be optimized for discrete epochs in life., (© 2016 Authors; published by Portland Press Limited.)