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https://www.readbyqxmd.com/read/28416741/relaxin-abrogates-renal-interstitial-fibrosis-by-regulating-macrophage-polarization-via-inhibition-of-toll-like-receptor-4-signaling
#1
Lei Chen, Ming-Lei Sha, Deng Li, Yi-Ping Zhu, Xing-Jie Wang, Chen-Yi Jiang, Shu-Jie Xia, Yi Shao
Renal fibrosis is a common feature of chronic kidney disease (CKD). To inhibit the CKD process, it is important to prevent renal fibrosis, though CKD remains incurable. Renal fibrosis can be inhibited by relaxin in several experimental models, but the mechanism of relaxin for antifibrotic potential is still not clear. And here we have studied the role of relaxin in macrophage polarization and renal inflammation after unilateral ureteral obstruction (UUO). Our results show that relaxin can downregulate the Toll-like receptor (TLR) 4 signaling, shift macrophage polarization toward the M2 phenotype and ameliorat renal fibrosis in the early stages of UUO...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28245243/serelaxin-as-a-potential-treatment-for-renal-dysfunction-in-cirrhosis-preclinical-evaluation-and-results-of-a-randomized-phase-2-trial
#2
Victoria K Snowdon, Neil J Lachlan, Anna M Hoy, Patrick W F Hadoke, Scott I Semple, Dilip Patel, Will Mungall, Timothy J Kendall, Adrian Thomson, Ross J Lennen, Maurits A Jansen, Carmel M Moran, Antonella Pellicoro, Prakash Ramachandran, Isaac Shaw, Rebecca L Aucott, Thomas Severin, Rajnish Saini, Judy Pak, Denise Yates, Neelesh Dongre, Jeremy S Duffield, David J Webb, John P Iredale, Peter C Hayes, Jonathan A Fallowfield
BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers...
February 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28009437/serelaxin-in-clinical-development-past-present-and-future
#3
REVIEW
Elaine Unemori
The availability of highly purified recombinant human relaxin, serelaxin, has enabled the conduct of clinical trials in several indications and the elucidation of its pharmacology in human subjects. These studies have demonstrated that serelaxin has unique hemodynamic properties that likely contribute to organ protection and long-term outcome benefits in acute heart failure. Clinical observations support its consideration for therapeutic use in other patient populations, including those with chronic heart failure, coronary artery disease, portal hypertension and acute renal failure...
December 23, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27727514/serelaxin-in-acute-heart-failure-most-recent-update-on-clinical-and-preclinical-evidence
#4
REVIEW
Raktim Kumar Ghosh, Kinjal Banerjee, Ramyashree Tummala, Somedeb Ball, Keyvan Ravakhah, Anjan Gupta
Heart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising healthcare costs and is one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long-term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone. Relaxin was discovered in pregnancy, but eventually found to have a number of other physiological actions, not only in pregnancy, but also in nonpregnant women and men...
February 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/27707703/the-enigma-of-continual-plasma-volume-expansion-in-pregnancy-critical-role-of-the-renin-angiotensin-aldosterone-system
#5
REVIEW
Crystal A West, Jennifer M Sasser, Chris Baylis
Pregnancy is characterized by avid renal sodium retention and plasma volume expansion in the presence of decreased blood pressure. Decreased maternal blood pressure is a consequence of reduced systemic vascular tone, which results from an increased production of vasodilators [nitric oxide (NO), prostaglandins, and relaxin] and decreased vascular responsiveness to the potent vasoconstrictor (angiotensin II). The kidneys participate in this vasodilatory response, resulting in marked increases in renal plasma flow and glomerular filtration rate (GFR) during pregnancy...
December 1, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/27629886/serelaxin-improves-the-pathophysiology-of-placental-ischemia-in-the-reduced-uterine-perfusion-pressure-rat-model-of-preeclampsia
#6
Jose A Santiago-Font, Lorena M Amaral, Jessica Faulkner, Tarek Ibrahim, Venkata Ramana Vaka, Mark W Cunningham, Babbette LaMarca
Preeclampsia is a hypertensive disorder of pregnancy that has limited therapeutic options. In healthy pregnancy, relaxin plays an important vasodilatory role to maintain vascular compliance; however, currently, there is no preclinical evidence to support the use of relaxin during preeclampsia. Therefore, the goal of this study was to test the hypothesis that recombinant human relaxin-2 (Serelaxin, Novartis; RLX) could reduce mean arterial pressure (MAP) and improve uterine artery resistance index (UARI) and nitric oxide bioavailability, and/or decrease prepro-endothelin-1 (PPET-1), soluble fms-like tyrosine kinase-1 (sFlt-1), and TNF-α) in the reduced uterine perfusion pressure (RUPP) model of preeclampsia...
December 1, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/27590257/vascular-actions-of-relaxin-nitric-oxide-and-beyond
#7
C H Leo, M Jelinic, H H Ng, S A Marshall, J Novak, M Tare, K P Conrad, L J Parry
The peptide hormone relaxin regulates the essential maternal hemodynamic adaptations in early pregnancy through direct actions on the renal and systemic vasculature. These vascular actions of relaxin occur mainly through endothelium-derived nitric oxide-mediated vasodilator pathways and improvements in arterial compliance in small resistance-size arteries. This work catalysed a plethora of studies which revealed quite heterogeneous responses across the different regions of the vasculature, and also uncovered nitric oxide-independent mechanisms of relaxin action...
September 2, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27489037/evidence-of-proteinuria-but-no-other-characteristics-of-pre-eclampsia-in-relaxin-deficient-mice
#8
Kelly P O'Sullivan, Sarah A Marshall, Scott Cullen, Tahnee Saunders, Natalie J Hannan, Sevvandi N Senadheera, Laura J Parry
Pre-eclampsia (PE) is a leading cause of maternal and fetal death, characterised by an imbalance of placental growth factors and hypertension at >20 weeks gestation. Impaired maternal systemic vascular adaptations and fetal growth restriction are features of both PE and pregnant relaxin-deficient (Rln-/-) mice. The aim of the present study was to investigate whether these phenotypes in Rln-/- mice are associated with abnormal placental growth factor expression, increased soluble fms-like tyrosine kinase-1 (sFlt-1), proteinuria and/or hypertension during pregnancy...
August 4, 2016: Reproduction, Fertility, and Development
https://www.readbyqxmd.com/read/27462268/involvement-of-cyclic-guanosine-monophosphate-dependent-protein-kinase-i-in-renal-antifibrotic-effects-of-serelaxin
#9
Veronika Wetzl, Elisabeth Schinner, Frieder Kees, Franz Hofmann, Lothar Faerber, Jens Schlossmann
INTRODUCTION: Kidney fibrosis has shown to be ameliorated through the involvement of cyclic guanosine monophosphate (cGMP) and its dependent protein kinase I (cGKI). Serelaxin, the recombinant form of human relaxin-II, increases cGMP levels and has shown beneficial effects on kidney function in acute heart failure patients. Antifibrotic properties of serelaxin are supposed to be mediated via relaxin family peptide receptor 1 and subsequently enhanced nitric oxide/cGMP to inhibit transforming growth factor-β (TGF-β) signaling...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27418970/serelaxin-for-the-treatment-of-acute-heart-failure-a-review-with-a-focus-on-end-organ-protection
#10
REVIEW
Javier Díez, Luis M Ruilope
Acute heart failure (AHF) is a complex clinical syndrome characterized by fluid overload and haemodynamic abnormalities (short-term clinical consequences) and the development of end-organ damage (long-term consequences). Current therapies for the treatment of AHF, such as loop diuretics and vasodilators, help to relieve haemodynamic imbalance and congestion, but have not been shown to prevent (and may even contribute to) end-organ damage, or to provide long-term clinical benefit. Serelaxin is the recombinant form of human relaxin-2, a naturally occurring hormone involved in mediating haemodynamic changes during pregnancy...
April 2016: European Heart Journal. Cardiovascular Pharmacotherapy
https://www.readbyqxmd.com/read/27385360/g-protein-coupled-receptors-as-potential-drug-candidates-in-preeclampsia-targeting-the-relaxin-insulin-like-family-peptide-receptor-1-for-treatment-and-prevention
#11
REVIEW
Kirk P Conrad
BACKGROUND: Important roles for G-protein-coupled receptors (GPCRs) have been identified in the maternal physiological adaptations to pregnancy and in the pathogenesis of preeclampsia. On this basis, GPCRs are potential therapeutic targets for preeclampsia. OBJECTIVES AND RATIONALE: In this review, vasopressin and apelin are initially considered in this context before the focus on the hormone relaxin and its cognate receptor, the relaxin/insulin-like family peptide receptor 1 (RXFP1)...
September 2016: Human Reproduction Update
https://www.readbyqxmd.com/read/27065874/the-anti-fibrotic-actions-of-relaxin-are-mediated-through-a-no-sgc-cgmp-dependent-pathway-in-renal-myofibroblasts-in-vitro-and-enhanced-by-the-no-donor-diethylamine-nonoate
#12
Chao Wang, Barbara K Kemp-Harper, Martina Kocan, Sheng Yu Ang, Tim D Hewitson, Chrishan S Samuel
INTRODUCTION: The anti-fibrotic hormone, relaxin, has been inferred to disrupt transforming growth factor (TGF)-β1/Smad2 phosphorylation (pSmad2) signal transduction and promote collagen-degrading gelatinase activity via a nitric oxide (NO)-dependent pathway. Here, we determined the extent to which NO, soluble guanylate cyclase (sGC) and cyclic guanosine monophosphate (cGMP) were directly involved in the anti-fibrotic actions of relaxin using a selective NO scavenger and sGC inhibitor, and comparing and combining relaxin's effects with that of an NO donor...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27039129/use-of-high-sensitivity-troponin-t-to-identify%C3%A2-patients-with-acute-heart-failure-at%C3%A2-lower%C3%A2-risk-for-adverse-outcomes-an-exploratory-analysis-from-the-relax-ahf-trial
#13
Peter S Pang, John R Teerlink, Adriaan A Voors, Piotr Ponikowski, Barry H Greenberg, Gerasimos Filippatos, G Michael Felker, Beth A Davison, Gad Cotter, Joshua Kriger, Margaret F Prescott, Tsushung A Hua, Thomas Severin, Marco Metra
OBJECTIVES: The aim of this study was to determine if a baseline high-sensitivity troponin T (hsTnT) value ≤99th percentile upper reference limit (0.014 μg/l ["low hsTnT"]) identifies patients at low risk for adverse outcomes. BACKGROUND: Approximately 85% of patients who present to emergency departments with acute heart failure are admitted. Identification of patients at low risk might decrease unnecessary admissions. METHODS: A post-hoc analysis was conducted from the RELAX-AHF (Serelaxin, Recombinant Human Relaxin-2, for Treatment of Acute Heart Failure) trial, which randomized patients within 16 h of presentation who had systolic blood pressure >125 mm Hg, mild to moderate renal impairment, and N-terminal pro-brain natriuretic peptide ≥1,600 ng/l to serelaxin versus placebo...
July 2016: JACC. Heart Failure
https://www.readbyqxmd.com/read/26936785/relaxin-deficiency-attenuates-pregnancy-induced-adaptation-of-the-mesenteric-artery-to-angiotensin-ii-in-mice
#14
Sarah A Marshall, Chen Huei Leo, Sevvandi N Senadheera, Jane E Girling, Marianne Tare, Laura J Parry
Pregnancy is associated with reduced peripheral vascular resistance, underpinned by changes in endothelial and smooth muscle function. Failure of the maternal vasculature to adapt correctly leads to serious pregnancy complications, such as preeclampsia. The peptide hormone relaxin regulates the maternal renal vasculature during pregnancy; however, little is known about its effects in other vascular beds. This study tested the hypothesis that functional adaptation of the mesenteric and uterine arteries during pregnancy will be compromised in relaxin-deficient (Rln(-/-)) mice...
May 1, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/26914675/chronic-nicotine-exposure-abolishes-maternal-systemic-and-renal-adaptations-to-pregnancy-in-rats
#15
Vanessa Meira Ferreira, Clevia Santos Passos, Edgar Maquigussa, Roberto Braz Pontes, Cassia Toledo Bergamaschi, Ruy Ribeiro Campos, Mirian Aparecida Boim
Pregnancy is characterized by maternal systemic and intrarenal vasodilation, leading to increases in the renal plasma flow (RPF) and glomerular filtration rate (GFR). These responses are mainly mediated by nitric oxide (NO) and relaxin. The impact of cigarette smoking on the maternal adaptations to pregnancy is unclear. Here we evaluated the effects of chronic exposure to nicotine on systemic and intrarenal parameters in virgin (V) and 14-day pregnant (P) Wistar rats. V and P groups received saline or nicotine (6 mg·kg(-1)·day(-1)) respectively, via osmotic minipumps for 28 days, starting 14 days before pregnancy induction...
2016: PloS One
https://www.readbyqxmd.com/read/26746861/relaxin-in-paraventricular-nucleus-contributes-to-sympathetic-overdrive-and-hypertension-via-pi3k-akt-pathway
#16
Hai-Jian Sun, Dan Chen, Ying Han, Ye-Bo Zhou, Jue-Jin Wang, Qi Chen, Yue-Hua Li, Xing-Ya Gao, Yu-Ming Kang, Guo-Qing Zhu
Relaxin is recognized as an ovarian polypeptide hormone. Abundant relaxin binding sites are observed in hypothalamic paraventricular nucleus (PVN). This study was conducted to determine the roles and underlying mechanisms of relaxin in the PVN in sympathetic activation and hypertension in spontaneously hypertensive rats (SHR). Experiments were performed in normotensive Wistar-Kyoto rats (WKY) and SHR. Relaxin and its RXFP1 receptors in PVN were up-regulated in SHR. Relaxin-positive neurons existed in both parvocellular and magnocellular parts of the PVN...
April 2016: Neuropharmacology
https://www.readbyqxmd.com/read/26603680/serelaxin-and-acute-heart-failure
#17
REVIEW
Jeremy Tietjens, John R Teerlink
Attempts at developing novel therapeutic agents for acute heart failure (AHF) over the past two decades have been marked by disappointment. Relaxin is a human peptide hormone believed to mediate many adaptive haemodynamic changes that occur during pregnancy. Because these effects may be useful for treating AHF, a recombinant version of human relaxin-2, serelaxin, has been developed as a novel therapeutic agent. Studies have confirmed serelaxin's haemodynamic effects of decreasing pulmonary and systemic resistance and increasing renal blood flow...
January 2016: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/26583301/targeted-biological-therapies-reach-the-heart-the-case-of-serelaxin-for-heart-failure
#18
REVIEW
V A Kumar, S S Wilson, S I Ayaz, P D Levy
Acute heart failure (AHF) is one of the most important causes of mortality, morbidity and rising healthcare costs. Despite this, there has been minimal advancement in the management of AHF and the treatment continues to focus on symptomatic improvement using vasodilators, diuretics and inotropes, none of which have shown any mortality benefits. Though originally thought of as a reproductive hormone, relaxin is now recognized as a potent vasodilator that modulates systemic and renal vascular tone, resulting in pre- and after-load reduction and a decrease in cardiac workload...
October 2015: Drugs of Today
https://www.readbyqxmd.com/read/26368576/chemically-synthesized-dicarba-h2-relaxin-analogues-retain-strong-rxfp1-receptor-activity-but-show-an-unexpected-loss-of-in-vitro-serum-stability
#19
Mohammed Akhter Hossain, Linda M Haugaard-Kedström, K Johan Rosengren, Ross A D Bathgate, John D Wade
Peptides and proteins are now acknowledged as viable alternatives to small molecules as potential therapeutic agents. A primary limitation to their more widespread acceptance is their generally short in vivo half-lives due to serum enzyme susceptibility and rapid renal clearance. Numerous chemical approaches to address this concern have been undertaken in recent years. The replacement of disulfide bonds with non-reducible elements has been demonstrated to be one effective means by eliminating the deleterious effect of serum reductases...
November 28, 2015: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/26333529/growth-differentiation-factor-15-gdf-15-in-patients-admitted-for-acute-heart-failure-results-from-the-relax-ahf-study
#20
RANDOMIZED CONTROLLED TRIAL
Gad Cotter, Adriaan A Voors, Margaret F Prescott, G Michael Felker, Gerasimos Filippatos, Barry H Greenberg, Peter S Pang, Piotr Ponikowski, Olga Milo, Tsushung A Hua, Min Qian, Thomas M Severin, John R Teerlink, Marco Metra, Beth A Davison
BACKGROUND: Growth differentiation factor 15 (GDF-15) was found to be upregulated in patients with chronic heart failure (HF) and associated with disease severity, however, data on patients with acute heart failure (AHF) is lacking. METHODS AND RESULTS: Levels of GDF-15 were measured at pre-specified time-points (baseline and at days 2, 5, 14, and 60) in patients enrolled in the placebo-controlled RELAXin in Acute Heart Failure (RELAX-AHF) study, which examined the effect of serelaxin in 1161 patients with AHF, systolic blood pressure >125 mmHg, and mild to moderate renal impairment...
November 2015: European Journal of Heart Failure
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