The Relaxin Gene‐Knockout Mouse: A Model of Progressive Fibrosis

Samuel, Chrishan S.; Zhao, Chenxu; Bathgate, Ross A. D.; Du, Xiaolan; Summers, Roger J.; Amento, Edward P.; Walker, Lesley; McBurnie, M.; Zhao, Ling; Tregear, Geoffrey W.

doi:10.1196/annals.1282.025

Cited by 89 publications

(58 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RLX exerts potent antifibrotic action and the RLX knockout mouse develops widespread fibrosis early in life (12). Chronically administered RLX preserves structure and function in the renal mass reduction and chronic angiotensin II infusion models of chronic kidney disease (13,14).…”

mentioning

confidence: 99%

An Emerging Role for Relaxin as a Renal Vasodilator

Sasser

Lindheimer

Baylis

2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

S triking renal and cardiovascular adaptations occur early in human pregnancy, including increases in intravascular volume and cardiac output. Despite these adaptations, and because of a marked reduction in systemic vascular resistance, blood pressure (BP) falls (1,2). One of the earliest and most dramatic changes is the increase in renal plasma flow (RPF) and GFR due to renal vasodilation (3). Animal studies indicate a role for the ovarian hormone relaxin (RLX) (4,5), and the report by Smith et al. (6) in this issue of JASN expands on this literature by reporting on the renal hemodynamic effect of acute RLX infusion in normal men and nonpregnant women.In human pregnancy, GFR and RPF are maximally increased (50% or more) by midterm, with the rise in RPF exceeding GFR; thus, the filtration fraction decreases. As expected, plasma creatinine declines, such that values Ͼ0.8 mg/dl are considered abnormal. Another striking change is the fall in plasma osmolality (P osm ) (3). Both adaptations are hallmarks of an "optimal" pregnancy, and the causes may be linked (1,3). The rat is useful to study mechanisms underlying renal adaptations to pregnancy because, similar to humans, rats exhibit renal vasodilation, hyperfiltration, and a fall in P osm during gestation. Micropuncture studies showed that the increase in GFR and RPF is due to parallel reductions in both afferent and efferent arteriolar resistances with no change in glomerular BP (3). Of note, studies using fractional dextran clearances combined with mathematical modeling suggest this to be the case in human gestation as well (3).The factors responsible for the increased gestational GFR and RPF are not entirely clear, although there is evidence of activation of the vasodilatory nitric oxide-cGMP signaling pathway (3). The renal vasodilatory stimulus is likely maternal in origin, because similar changes are observed in pseudopregnant rats (3) and on a smaller scale during the luteal phase of the menstrual cycle (2,3).As mentioned above, studies in the rat have identified ovarian RLX as an important mediator of renal vasodilation, hyperfiltration, and osmoregulation. Chronic administration of RLX in virgin female rats causes renal vasodilation, increased GFR, and decreased P osm with no change in BP (7). The RLX-induced increase in GFR and RPF and fall in P osm is independent of other ovarian hormones as this effect was also observed in ovariectomized female and male rats (4,7).Relaxin appears to be essential for the renovascular adaptations of rat pregnancy. A key study by Novak et al. demonstrated that removal of circulating RLX by ovariectomy or by administration of neutralizing antibodies to rat RLX abolished the rise in GFR and RPF and fall in P osm and prevented the reduction in myogenic activity in small renal arteries in midterm pregnant rats (5).In women, RLX levels rise during the luteal phase of the menstrual cycle, when GFR is at its maximum, and increase further when stimulated by human chorionic gonadotrophin during early pregnancy (8), concurrent wit...

show abstract

mentioning

confidence: 99%

An Emerging Role for Relaxin as a Renal Vasodilator

Sasser

Lindheimer

Baylis

2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…These data demonstrate, for the first time, the antifibrotic actions of Insl6. In comparison, the antifibrosis effect of relaxin‐2 has been well characterized 46, 47. Relaxin‐2 knockout mice display age‐dependent increases in fibrosis in the heart, lung, kidney, and reproductive systems 46.…”

Section: Discussionmentioning

confidence: 99%

“…In comparison, the antifibrosis effect of relaxin‐2 has been well characterized 46, 47. Relaxin‐2 knockout mice display age‐dependent increases in fibrosis in the heart, lung, kidney, and reproductive systems 46. At the cellular level, relaxin‐2 administration has been shown to counteract the effects of transforming growth factor‐β or AngII on fibroblast proliferation and differentiation, reduce collagen secretion, and promote matrix metalloproteinase activities 48.…”

Section: Discussionmentioning

confidence: 99%

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

Maruyama

Yoshida

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundThe insulin/insulin‐like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin‐2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin‐like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss‐of‐function and protein delivery methods.Methods and ResultsInsl6‐deficient and wild‐type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6‐knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6‐knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis‐associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol‐challenged hearts treated with INSL6 protein.ConclusionsEndogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II– and isoproterenol‐induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis.

show abstract

“…[98][99][100] Targeted disruption of the relaxin gene results in development of age-related fibrosis in many tissues, including heart, lungs, kidney, skin, and reproductive tract. 101 Using animal models of fibrosis, treatment with relaxin showed effectiveness in the reduction of fibrosis in experimental models of cardiac disease. 79,[102][103][104][105][106] In addition, relaxin has shown effectiveness in the treatment of models of pulmonary, renal, and hepatic fibrosis.…”

mentioning

confidence: 99%

Current treatments for acute heart failure: focus on serelaxin

Bennett¹

2014

RRCC

View full text Add to dashboard Cite

Acute heart failure remains an enormous health concern worldwide, and is a major cause of death and hospitalization. In spite of this, the treatment strategies for acute heart failure have remained largely unchanged for the past 2 decades. Several large randomized, placebocontrolled clinical trials have recently been conducted to attempt to improve the treatment and outcomes of acute decompensated heart failure. Some studies, including the EVEREST (tolvaptan) and ASCEND (nesiritide) showed efficacy at relieving early symptoms, but failed to improve long-term outcomes. Others, including PROTECT (rolofylline) and ASTRONAUT (aliskiren) showed little benefit in the relief of early symptoms or long-term outcomes. The recent RELAX-AHF studies using serelaxin, a recombinant form of relaxin, have shown considerable promise. Importantly, serelaxin improved congestion (dyspnea) and other early targets of acute decompensated heart failure treatment, but also improved mortality at 180 days. The purpose of this review is to provide an overview of current treatment strategies for acute decompensated heart failure, and a discussion of the recent clinical trials, with an emphasis on the serelaxin studies.

show abstract

The Relaxin Gene‐Knockout Mouse: A Model of Progressive Fibrosis

Cited by 89 publications

References 25 publications

An Emerging Role for Relaxin as a Renal Vasodilator

An Emerging Role for Relaxin as a Renal Vasodilator

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

Current treatments for acute heart failure: focus on serelaxin

Contact Info

Product

Resources

About