Relaxin-2 Does Not Ameliorate Nephropathy in an Experimental Model of Type-1 Diabetes

Dschietzig, Thomas; Krause-Relle, Katharina; Hennequin, Maud; Websky, Karoline von; Rahnenführer, Jan; Ruppert, Jana; Grön, Hans Jürgen; Armbruster, Franz Paul; Bathgate, Ross A. D.; Aschenbach, Jörg R.; Forssmann, Wolf‐Georg; Hocher, Berthold

doi:10.1159/000368484

Cited by 18 publications

(11 citation statements)

References 57 publications

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“…Serelaxin treatment for the final two weeks of diabetes did not impact these metabolic parameters. Our findings are similar to a previous study which reported serelaxin had no effects on blood glucose levels in Type 1 diabetic mice31. However, in a mouse model of Type 2 diabetes, serelaxin reduced blood glucose levels3032.…”

Section: Discussionsupporting

confidence: 92%

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

Leo

Prakoso

et al. 2017

Sci Rep

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Serelaxin prevents endothelial dysfunction in the mouse aorta ex vivo and inhibits apoptosis in cardiomyocytes under acute hyperglycaemia. Less is known about the effects of serelaxin in an in vivo mouse model of diabetes. Therefore, we tested the hypothesis in streptozotocin (STZ)-treated mice that serelaxin is able to reverse diabetes-induced vascular dysfunction and cardiac remodelling. Mice were divided into citrate buffer + placebo, STZ + placebo and STZ + serelaxin (0.5 mg/kg/d, 2 weeks) groups. After 12 weeks of diabetes, sensitivity to the endothelium-dependent agonist acetylcholine (ACh) was reduced in the mesenteric artery. This was accompanied by an enhanced vasoconstrictor prostanoid contribution and a decrease in endothelium-derived hyperpolarisation (EDH)-mediated relaxation. Serelaxin restored endothelial function by increasing nitric oxide (NO)-mediated relaxation but not EDH. It also normalised the contribution of vasoconstrictor prostanoids to endothelial dysfunction and suppressed diabetes-induced hyper-responsiveness of the mesenteric artery to angiotensin II. Similarly, diabetes reduced ACh-evoked NO-mediated relaxation in the aorta which was reversed by serelaxin. In the left ventricle, diabetes promoted apoptosis, hypertrophy and fibrosis; serelaxin treatment reversed this ventricular apoptosis and hypertrophy, but had no effect on fibrosis. In summary, serelaxin reversed diabetes-induced endothelial dysfunction by enhancing NO-mediated relaxation in the mouse vasculature and attenuating left ventricular hypertrophy and apoptosis.

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Section: Discussionsupporting

confidence: 92%

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

Leo

Prakoso

et al. 2017

Sci Rep

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“…However, rhRLX may not be universally renoprotective, as it did not prevent diabetic renal complications in mouse models of type I diabetes (Wong et al , ; Dschietzig et al , ), when TGF‐β1 was not elevated in either model. Importantly, in a phase II scleroderma trial (Khanna et al , ), cessation of rhRLX after 24 weeks of administration resulted in a significant decline in renal function, as estimated by creatinine clearance (Khanna et al , ).…”

Section: Anti‐fibrotic Actions Of Relaxin In the Kidneymentioning

confidence: 99%

“…These effects are only partially dose‐dependent, with robust effects seen at physiological concentrations (Mookerjee et al , ). Importantly, the anti‐fibrotic actions of rhRLX may well be contingent on TGF‐β1, which may explain the lack of efficacy in models without aberrant TGF‐β1 expression (Wong et al , ; Dschietzig et al , ).…”

Section: Anti‐fibrotic Actions Of Relaxin In the Kidneymentioning

confidence: 99%

Anti‐fibrotic actions of relaxin

Samuel

Royce

Hewitson

et al. 2016

British J Pharmacology

114

115

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Fibrosis refers to the hardening or scarring of tissues that usually results from aberrant wound healing in response to organ injury, and its manifestations in various organs have collectively been estimated to contribute to around 45-50% of deaths in the Western world. Despite this, there is currently no effective cure for the tissue structural and functional damage induced by fibrosisrelated disorders. Relaxin meets several criteria of an effective anti-fibrotic based on its specific ability to inhibit pro-fibrotic cytokine and/or growth factor-mediated, but not normal/unstimulated, fibroblast proliferation, differentiation and matrix production. Furthermore, relaxin augments matrix degradation through its ability to up-regulate the release and activation of various matrix-degrading matrix metalloproteinases and/or being able to down-regulate tissue inhibitor of metalloproteinase activity. Relaxin can also indirectly suppress fibrosis through its other well-known (anti-inflammatory, antioxidant, antihypertrophic, anti-apoptotic, angiogenic, wound healing and vasodilator) properties. This review will outline the organ-specific and general anti-fibrotic significance of exogenously administered relaxin and its mechanisms of action that have been documented in various non-reproductive organs such as the cardiovascular system, kidney, lung, liver, skin and tendons. In addition, it will outline the influence of sex on relaxin's anti-fibrotic actions, highlighting its potential as an emerging anti-fibrotic therapeutic. LINKED ARTICLESThis article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc Abbreviations α-SMA, α-smooth muscle actin; AT 2 receptor, angiotensin type 2 receptor; CCl 4 , carbon tetrachloride; ECM, extracellular matrix; HSC, hepatic stellate cell; INSL, insulin-like; KO, knockout; MSC, mesenchymal stem cell; PMA, phorbol 12-myristate 13-acetate; RLN, relaxin gene; rhRLX, synthetically or recombinantly produced drug form of relaxin; RXFP1, relaxin family peptide receptor 1; TIMP, tissue inhibitor of metalloproteinase IntroductionThe tissue response to stress depends on a number of intrinsic and extrinsic factors including the length and extent of injury. When injury or disease is mild or transient, then the tissue response leads to remodelling or regeneration of the organ parenchyma. However, if the injury is either severe or prolonged, the process is characterized by ongoing inflammation and extracellular matrix (ECM) production. Fibrosis is therefore a failure of the wound healing process, where ECM synthesis is ongoing (Wynn, 2008;Hewitson, 2009). This maladaptive response is particularly dependent on paracrine and autocrine production of TGF-β1 and the consequent recruitment of activated fibroblasts (myofibroblasts). Over-abundant ECM production and failure to resolve lead to significant organ damage and dysfunction, wh...

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“…Relaxin reduced unilateral uteretic obstruction-induced renal disease by antagonizing the effect of TGF-β, and that this effect was enhanced by coadministration of mesenchymal stem cells (Hewitson et al, 2010; Huuskes et al, 2015). On the other hand, relaxin was not effective in a diabetes-related renal disease model (Wong et al, 2013; Dschietzig et al, 2015). However, unlike the unilateral uteretic obstruction models, TGFβ was not increased in the diabetic model.…”

Section: Relaxinmentioning

confidence: 97%

Novel Anti-fibrotic Therapies

McVicker

Bennett

2017

Front. Pharmacol.

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Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Novel treatments have recently been identified that hold promise as potential therapeutic agents for cardiovascular diseases associated with fibrosis, as well as other fibrotic conditions. The purpose of this review is to provide an overview of emerging antifibrotic agents that have shown encouraging results in preclinical or early clinical studies, but have not yet been approved for use in human disease. One of these agents is bone morphogenetic protein-7 (BMP7), which has beneficial effects in multiple models of fibrotic disease. Another approach discussed involves altering the levels of micro-RNA (miR) species, including miR-29 and miR-101, which regulate the expression of fibrosis-related gene targets. Further, the antifibrotic potential of agonists of the peroxisome proliferator-activated receptors will be discussed. Finally, evidence will be reviewed in support of the polypeptide hormone relaxin. Relaxin is long known for its extracellular remodeling properties in pregnancy, and is rapidly emerging as an effective antifibrotic agent in a number of organ systems. Moreover, relaxin has potent vascular and renal effects that make it a particularly attractive approach for the treatment of cardiovascular diseases. In each case, the mechanism of action and the applicability to various fibrotic diseases will be discussed.

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Relaxin-2 Does Not Ameliorate Nephropathy in an Experimental Model of Type-1 Diabetes

Cited by 18 publications

References 57 publications

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

Anti‐fibrotic actions of relaxin

Novel Anti-fibrotic Therapies

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