Mechanisms of anti-VEGF therapy-induced kidney injury:current insights and future perspectives in combination with immune checkpoint inhibitors

The formation of new blood vessels is crucial for tumour and metastatic progression. Consequently, targeted therapies directed towards the vascular endothelial growth factor (VEGF) pathway have significantly improved treatment outcomes in several malignancies. These treatment modalities are frequently used in current oncologic practice, as monotherapy, or in combination with other anti-cancer regimens such as immune checkpoint inhibitors (ICIs), to enhance the anti-cancer effects. Despite their proven efficacy, anti-VEGF therapies are also known to cause substantial renal toxicity. Common renal side effects include hypertension, proteinuria, renal dysfunction, thrombotic microangiopathy, and in some cases, renal failure. These adverse effects pose significant challenges in clinical practice, as kidney damage can lead to lower dosing of anti-cancer treatment and compromise quality of life. The mechanisms underlying kidney toxicity associated with anti-VEGF therapies, including in combination with ICIs, are poorly understood. A deeper understanding of these mechanisms is essential for mitigating kidney damage and preserving kidney function during treatment. This review aims to explore the role of VEGF in renal physiology, the incidence of renal toxicities associated with anti-VEGF therapies, and the potential mechanisms driving these toxicities, with particular emphasis on the endothelin, nitric oxide, and prostanoid pathways. Additionally, the review will address the renal effects observed when anti-VEGF therapies are combined with ICIs, as both treatment modalities are independently associated with kidney-related adverse effects, along with the underlying mechanisms involved.</p

Targeting angiotensinogen with RNA-based therapeutics

PURPOSE OF REVIEW: To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases. RECENT FINDINGS: Liver-targeted, stable antisense oligonucleotides and small interfering RNA targeting angiotensinogen are now available, and may allow treatment with at most a few injections per year, thereby improving adherence. Promising results have been obtained in hypertensive animal models, as well as in rodent models of atherosclerosis, polycystic kidney disease and pulmonary fibrosis. The next step will be to evaluate the optimal degree of suppression, synergy with existing renin-angiotensin-aldosterone system blockers, and to determine harmful effects of suppressing angiotensinogen in the context of common comorbidities, such as heart failure and chronic kidney disease. SUMMARY: Targeting angiotensinogen with RNA-based therapeutics is a promising new tool to treat hypertension and diseases beyond. Their long-lasting effects are particularly exciting, and if translated to a clinical application of at most a few administrations per year, may help to eliminate nonadherence

Cyclooxygenase-2 inhibition prevents renal toxicity but not hypertension during sunitinib treatment

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 (PGI2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 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 PGI2 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 &lt; 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 PGI2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P &lt; 0.001), but not circulating PGI2 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 PGI2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential.</p

Cardiovascular workforce sustainability sector consultation: Recommendations from an Australian stakeholder summit

In 2023, a joint National Cardiovascular Workforce Sustainability Summit was convened by the Australian Cardiovascular Alliance (ACvA), the Cardiac Society of Australia and New Zealand, and the National Heart Foundation of Australia, to facilitate a national conversation towards developing a workforce sustainability strategy within the cardiovascular research sector. This initiative stemmed from a previous study conducted by the ACvA which revealed that almost 70% of early and mid-career cardiovascular researchers surveyed had contemplated leaving the sector. Summit attendees reported sector-wide challenges to career progression and retention across three key themes: 1) well-being and career satisfaction, 2) learning and development, and 3) resource allocation. The summit also identified a need for greater collaboration and multidisciplinary approaches to research to foster growth towards a more sustainable sector. Key recommendations from the Summit included: 1) establish metrics to monitor progress towards a more sustainable sector and signpost improvement in workforce sustainability; 2) establish a collective partnership between central bodies for unified advocacy and monitoring of metrics; and 3) develop a collaborative, strategic and targeted approach to guide and facilitate training programs that have been developed by shared sector-wide philosophy

Aspirin for the prevention and treatment of pre-eclampsia: A matter of COX-1 and/or COX-2 inhibition?

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 im

Zinc is a critical regulator of placental morphogenesis and maternal hemodynamics during pregnancy in mice

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.Rebecca L. Wilson, Shalem Y. Leemaqz, Zona Goh, Dale McAninch, Tanja Jankovic- Karasoulos, Gabriela E. Leghi, Jessica A. Phillips, Katrina Mirabito Colafella, Cuong Tran, Sean O’Leary, Sam Buckberry, Stephen Pederson, Sarah A. Robertson, Tina Bianco-Miotto, Claire T. Robert

Extragonadal Effects of Follicle-Stimulating Hormone on Osteoporosis and Cardiovascular Disease in Women during Menopausal Transition

The risk of osteoporosis and cardiovascular disease increases significantly in postmenopausal women. Until recently, the underlying mechanisms have been primarily attributed to estrogen decline following menopause. However, follicle-stimulating hormone (FSH) levels rise sharply during menopausal transition and are maintained at elevated levels for many years. FSH receptor has been detected in various extragonadal sites, including osteoclasts and endothelial cells. Recent advances suggest FSH may contribute to postmenopausal osteoporosis and cardiovascular disease. Here, we review the key actions through which FSH contributes to the risk of osteoporosis and cardiovascular disease in women as they transition through menopause. Advancing our understanding of the precise mechanisms through which FSH promotes osteoporosis and cardiovascular disease may provide new opportunities for improving health-span for postmenopausal women

Selective ETA vs. Dual ETA/B receptor blockade for the prevention of sunitinib-induced hypertension and albuminuria in WKY rats

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 antihypertensive 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