Effect of Relaxin in Two Models of Renal Mass Reduction

Garber, Sandra L.; Mirochnik, Yelena; Brecklin, Carolyn; Slobodskoy, Leonid; Arruda, José A.L.; Dunea, George

doi:10.1159/000066302

Cited by 63 publications

(50 citation statements)

References 15 publications

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“…30 In separate studies, H2 relaxin inhibited renal interstitial fibrosis and improved glomerular filtration rate in an experimental bromoethylamine rat model 33 and two rat models of renal mass reduction caused by infarction or surgical excision of both poles. 34 Consistent with these findings, H2 relaxin was demonstrated to inhibit collagen content and staining in a carbon tetrachloride-induced rat model of hepatic fibrosis 31 and markedly decreased, by 40%-90%, left ventricular collagen concentration in three rodent models of established cardiac fibrosis caused by relaxin-deficiency, 22 transgenic overexpression of β2-adrenoreceptors 22 or hypertension. 35 In all of these models, increased collagen deposition had to be induced by surgical, chemical or genetically modified means to be effectively treated by relaxin.…”

Section: The Effects Of Relaxin Administration To Models Of Induced Fmentioning

confidence: 55%

Relaxin: Antifibrotic Properties and Effects in Models of Disease

Samuel

2005

Clinical Medicine & Research

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Fibrosis (progressive scarring) is a leading cause of organ failure worldwide and causes loss of organ function when normal tissue is replaced with excess connective tissue. Several organs are prone to this process regardless of etiology. The pleiotropic hormone, relaxin, is emerging as a novel antifibrotic therapy. Relaxin has been shown to limit collagen production and reorganization, while stimulating increased collagen degradation. It not only prevents fibrogenesis, but also reduces established scarring.This review summarizes (1) the levels at which relaxin inhibits collagen production and existing collagen overexpression in induced models of fibrosis, and (2) the collagen-related phenotypes of relaxin-and LGR7-deficient mice. Recent studies on relaxin-deficient mice have established relaxin as an important, naturally occurring regulator of collagen turnover and provide new insights into the therapeutic potential of relaxin. Keywords: Collagen, Gene-knockout mice, Fibrosis, RelaxinOne of the most consistent biological effects of relaxin is its ability to stimulate the breakdown of collagen, a major component of all organs within the body. Relaxin not only stimulates collagen remodeling within the birth canal in preparation for parturition, 1 but acts on cells and tissues to inhibit fibrosis, the process of tissue scarring which is primarily the result of excessive collagen deposition.Fibrosis is a universal response to chronic injury and inflammation of several organs and manifests itself as excess accumulation of connective tissue resulting in an irreversible loss of tissue function when normal tissue is replaced by scar tissue. 12,13 Fibrosis exists in numerous forms, including vascular sclerosis, hepatic cirrhosis, pulmonary fibrosis and renal fibrosis. These forms of deep organ fibrosis are particularly serious because the progressive loss of organ function is a leading cause of mortality estimated to account for 45% of deaths in the United States between 1984 and 1989. 12 It is also noteworthy that the underlying pathology of fibrosis remains similar in all cases suggesting that insights into the pathogenesis of scarring in any one of these organs has important implications for our understanding of fibrosis in general.Rel axin is a dimeric peptide hormone that is structurally related to the insulin family of peptides and has a diverse range of biological actions in several species. 1-9 Discovered almost 80 years ago, relaxin was found to be primarily produced in the ovary and/or placenta during pregnancy and was initially regarded as a hormone of pregnancy. 1 Humans and higher primates have three relaxin genes, designated as H1, H2 and H3 relaxin, 10 while two relaxin genes, relaxin-1 and relaxin-3, exist in rodents and are equivalent to H2 and H3 relaxin, respectively. The H2 relaxin protein (or relaxin-1 in rodents) is the major circulating and stored form of relaxin in each respective species and, therefore, will be the forms of relaxin referred to in this review. The H3 relaxin gene (or relaxin-3 ...

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Section: The Effects Of Relaxin Administration To Models Of Induced Fmentioning

confidence: 55%

Relaxin: Antifibrotic Properties and Effects in Models of Disease

Samuel

2005

Clinical Medicine & Research

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“…6 However, prospective controlled studies on the renal hemodynamic effects of serelaxin in patients with heart failure, using the gold standard methods for measuring GFR and RPF, are lacking. We assessed, therefore, the renal hemodynamic effects of serelaxin in patients with symptomatic CHF, impaired renal function, and a baseline systolic blood pressure (SBP) ≥110 mm Hg.…”

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confidence: 99%

Renal Hemodynamic Effects of Serelaxin in Patients With Chronic Heart Failure

Voors

Dahlke

Meyer

et al. 2014

Circ: Heart Failure

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Background— Serelaxin is a promising therapy for acute heart failure. The renal hemodynamic effects of serelaxin in patients with chronic heart failure are unknown. Methods and Results— In this double-blind, randomized, placebo-controlled, multicenter study, patients with New York Heart Association Class II to III chronic heart failure, left ventricular ejection fraction ≤45%, and estimated glomerular filtration rate (GFR) 30 to 89 mL/min per 1.73 m 2 received intravenous serelaxin 30 μg/kg per day or placebo for 24 hours. Primarily, we assessed the difference between serelaxin and placebo on renal plasma flow (para-aminohippuric acid clearance) and GFR (iothalamate clearance) over 8 to 24 hours. All 22 patients from 1 clinical site were excluded from primary analyses before unblinding because of implausible measurements. The primary analysis comprised 65 patients, mean age was 68 (±10) years, 89% were male, mean estimated GFR was 64 (±19) mL/min per 1.73 m 2 , and 34% had New York Heart Association Class III symptoms. Renal plasma flow increased by 29% with serelaxin and 14% with placebo (13% relative increase with serelaxin; P =0.0386), whereas GFR changes did not differ significantly during 8 to 24 hours. Filtration fraction increased by 36% with serelaxin and 62% with placebo (16% relative decrease with serelaxin; P =0.0019) during 8 to 24 hours. Changes in systolic blood pressure were largely similar, and creatinine clearance did not differ between groups. Adverse event rates were similar with serelaxin (20.5%) and placebo (25.0%). Conclusions— In patients with chronic heart failure, serelaxin increased renal plasma flow and reduced the increase in filtration fraction compared with placebo, but did not affect GFR. These results suggest beneficial renal hemodynamic effects in patients with chronic heart failure. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01546532.

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“…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). Perhaps most impressively, only 20 d of RLX administration reverses some of the structural damage and functional declines seen in the aging rat (15).…”

mentioning

confidence: 99%

An Emerging Role for Relaxin as a Renal Vasodilator

Sasser

Lindheimer

Baylis

2006

Journal of the American Society of Nephrology

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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...

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Effect of Relaxin in Two Models of Renal Mass Reduction

Cited by 63 publications

References 15 publications

Relaxin: Antifibrotic Properties and Effects in Models of Disease

Relaxin: Antifibrotic Properties and Effects in Models of Disease

Renal Hemodynamic Effects of Serelaxin in Patients With Chronic Heart Failure

An Emerging Role for Relaxin as a Renal Vasodilator

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