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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 fibrosis-related 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, anti-hypertrophic, 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 Articles This 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 [ABSTRACT FROM AUTHOR]

The "Developmental Origins of Health and Disease" hypothesis has caused resurgence of interest in understanding the factors regulating fetal development. A multitude of prenatal perturbations may contribute to the onset of diseases in adulthood including cardiovascular and renal diseases. Using animal models such as maternal glucocorticoid exposure, maternal calorie or protein restriction and uteroplacental insufficiency, studies have identified alterations in kidney development as being a common feature. The formation of a low nephron endowment may result in impaired renal function and in turn may contribute to disease. An interesting feature in many animal models of developmental programming is the disparity between males and females in the timing of onset and severity of disease outcomes. The same prenatal insult does not always affect males and females in the same way or to the same degree. Recently, our studies have focused on changes induced in the kidney of both the fetus and the offspring, following a perturbation during pregnancy. We have shown that changes in the renin-angiotensin system (RAS) occur in the kidney. The changes are often sex specific which may in part explain the observed sex differences in disease outcomes and severity. This review explores the evidence suggesting a critical role for the RAS in sex specific developmental programming of disease with particular reference to the immediate and long term changes in the local RAS within the kidney., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Common pregnancy complications are associated with impaired placental development. This study aimed to characterise the ontogeny of structural correlates of rabbit placental function, its expression of genes encoding components of the renin-angiotensin system (RAS), as well as 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) mRNA since these are known to be expressed by the placenta and are associated with pregnancy complications, including preeclampsia and intrauterine programming. Placentae were collected at gestational age (GA) 14, 21 and 28 (term=32 days). Gene expression was analysed using real time PCR and placental structures were quantified via image analyses. The volume densities and volumes of trophoblast, fetal capillaries, maternal blood space, surface density and surface area of trophoblast all progressively increased, while the arithmetic mean barrier thickness of trophoblast decreased across gestation. Maternal plasma renin activity (PRA) was positively correlated with volumes of trophoblast and maternal blood space, surface density and surface area of trophoblast. Placental renin mRNA declined ( downward arrow62%; P<0.01) across gestation and was negatively correlated with maternal PRA (GA0), fetal and placental weights, placental angiotensin type 1 and 2 receptors (AT(1)R and AT(2)R) mRNA and volume of trophoblast. AT(1)R mRNA expression was increased by 92% (P<0.001) across gestation. AT2R mRNA expression was approximately 81% (P<0.01) greater at GA14 compared to GA21. Placental 11beta-HSD2 mRNA expression was approximately 74% greater (P<0.01) at GA21 than GA14, but by GA28 was similar to that at GA14. These data show that changes in placental gene expression are associated with key events in placental and fetal development, indicating that the rabbit provides a good model for investigations of pregnancy perturbations that alter the RAS or programme the fetus.

Previously, we demonstrated that adult blood pressure was increased in offspring of rabbit mothers with chronic secondary renal hypertension. Our study identified sex-specific differences in the programming of hypertension, with female, not male, offspring, having increased blood pressure at 30 wk of age. The aim of this study was to characterize the maternal hypertension during pregnancy to determine potential programming stimuli. Further, we examined the impact of chronic maternal hypertension on offspring birth weight, nephron number, and renal noradrenaline content (as an index of renal innervation density). Three groups of mothers and their offspring were studied: two-kidney, one-wrap (2K-1W, n = 9 mothers) hypertensive, two-kidney, two-wrap (2K-2W, n = 8) hypertensive, and a sham-operated group (n = 9). Mean arterial blood pressure was increased by approximately 20 mmHg throughout pregnancy in both hypertensive groups compared with sham mothers (P(G) < 0.001). Plasma renin activity (PRA; P(G) < 0.05) and aldosterone (P(G) < 0.05) levels were increased during gestation in the 2K-1W, but not the 2K-2W mothers. Birth weight was increased by approximately 20% in offspring of both groups of hypertensive mothers (P(T) < 0.001), though this was associated with a reduction in litter size. Renal noradrenaline content was increased ( approximately 40%, P < 0.05) at 5 wk of age in female 2K-1W offspring compared with sham offspring. Glomerular number was not reduced in female offspring of either group of hypertensive mothers; however, glomerular tuft volume was reduced in female 2K-2W offspring (P < 0.05), indicative of a reduction in glomerular filtration surface area. In conclusion, the two models of renal hypertension produced differential effects on the offspring. The impact of a stimulated maternal renin-angiotensin system in the 2K-1W model of hypertension may influence development of the renal sympathetic nerves and contribute to programming of adult hypertension.

1. The aim of the present study was to determine the effects of the metalloendopeptidase (EP) 24.15 and 24.16 inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA-2) on haemodynamics and renal function in conscious rabbits with two-kidney, two-wrapped hypertension. We have also examined the role of endogenous bradykinin in the maintenance phase of this form of renovascular hypertension and whether inhibition of bradykinin degradation contributes to any potential effects of JA-2. 2. In two preliminary operations, rabbits were equipped with transit-time ultrasound flow probes for measuring cardiac output (CO) and renal blood flow (RBF) and had both kidneys wrapped in cellophane. Starting 4 weeks after the last operation, rabbits underwent four studies (3-5 days apart), during which they were treated with combinations of the bradykinin B2 receptor antagonist icatibant or its vehicle (1 mL/kg bodyweight 0.9% w/v NaCl) and JA-2 or its vehicle (1 mL/kg of a 5% w/v 2-hydroxypropyl-beta-cyclodextrin, 2.5% v/v dimethylsulphoxide solution). Renal function was monitored using standard renal clearance methods. 3. Icatibant (10 microg/kg) had no significant effects on systemic haemodynamic variables (mean arterial pressure, heart rate or CO), renal haemodynamic variables (RBF or glomerular filtration rate), urine flow or sodium excretion. At 5 mg/kg plus 3 mg/kg per h, JA-2 also did not affect any of these variables, either after icatibant vehicle treatment or after icatibant treatment. 4. Our data do not support major roles for endogenous bradykinin or bradykinin degradation by EP 24.15/24.16 in the control of systemic and renal haemodynamics or renal excretory function in two-kidney, two-wrapped hypertension in rabbits.

The role of renal sympathetic nerve activity (RSNA) in the physiological regulation of medullary blood flow (MBF) remains ill defined, yet regulation of MBF may be crucial to long-term arterial pressure regulation. To investigate the effects of reflex increases in RSNA on intrarenal blood flow distribution, we exposed pentobarbital sodium-anesthetized, artificially ventilated rabbits (n = 7) to progressive hypoxia while recording RSNA, cortical blood flow (CBF), and MBF using laser-Doppler flowmetry. Another group of animals with denervated kidneys (n = 6) underwent the same protocol. Progressive hypoxia (from room air to 16, 14, 12, and 10% inspired O(2)) significantly reduced arterial oxygen partial pressure (from 99 +/- 3 to 65 +/- 2, 51 +/- 2, 41 +/- 1, and 39 +/- 2 mmHg, respectively) and significantly increased RSNA (by 8 +/- 3, 44 +/- 25, 62 +/- 21, and 76 +/- 37%, respectively, compared with room air) without affecting mean arterial pressure. There were significant reductions in CBF (by 2 +/- 1, 5 +/- 2, 11 +/- 3, and 14 +/- 2%, respectively) in intact but not denervated rabbits. MBF was unaffected by hypoxia in either group. Thus moderate reflex increases in RSNA cause renal cortical vasoconstriction, but not at vascular sites regulating MBF.

Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation.

The medullary microcirculation receives only about 10% of total renal blood flow, but plays a critical role in long-term arterial pressure regulation, so we need to better understand its regulation. Although there is evidence that circulating and locally acting hormones can differentially affect cortical and medullary blood flow in anaesthetized animals, there is little information from studies in conscious animals. This study is aimed (i) to develop a method for chronic measurement of cortical and medullary blood flow in conscious rabbits, and (ii) to test whether renal cortical and medullary blood flow can be differentially affected by intravenous (i.v.) infusions of various vasoconstrictor hormones in conscious rabbits. At preliminary operations, rabbits were equipped with single-fibre laser-Doppler flowprobes in the (left) renal cortex and medulla, and Transonic flowprobes for measuring cardiac output and renal blood flow. Intravenous angiotensin II (300 ng kg(-1) min(-1)), [Phe2,Ile3,Orn8]-vasopressin (30 ng kg(-1) min(-1)), noradrenaline (300 ng kg(-1) min(-1)), endothelin-1 (20 ng kg(-1) min(-1)) and N G-nitro-L-arginine (10 mg kg(-1)) increased mean arterial pressure (by 10-45% of baseline) and reduced heart rate (by 16-35%) and cardiac output (by 16-45%). Consistent with previous observations in anaesthetized rabbits, all treatments except [Phe2,Ile3, Orn8]-vasopressin reduced renal blood flow (13-63%) and cortical blood flow (16-47%), but medullary blood flow was significantly reduced only by [Phe2,Ile3,Orn8]-vasopressin (41%) and N G-nitro-L-arginine (42%). The diversity of these responses of cortical and medullary blood flow to i.v. infusions of vasoconstrictors provides further evidence for physiological roles of circulating and local hormones in the differential regulation of regional kidney blood flow.

The diversity of renal arteriole diameters in different cortical regions has important consequences for control of glomerular capillary pressure. We examined whether intrarenal angiotensin II (ANG II; 0.1, 1, or 5 ng. kg(-1). min(-1)) in anesthetized rabbits acts preferentially on pre- or postglomerular vessels using vascular casting. ANG II produced dose-related reductions in afferent and efferent diameters in the outer, mid, and inner cortex, without effecting arterial pressure. Afferent diameter decreased more than efferent in the outer and mid cortex (P < 0.05) but by a similar extent in juxtamedullary nephrons (P = 0.58). Calculated efferent resistance increased more than afferent, especially in the outer cortex (127 vs. 24 units; 5 ng. kg(-1). min(-1) ANG II). ANG II produced significant dose-related increases in the distance between the arterioles at the entrance to the glomerular pole in all regions. Thus afferent diameter decreased more in response to ANG II, but efferent resistance rose more due to smaller resting luminal dimensions. The results also indicate that glomerular pole dimensions change in response to ANG II.

We tested for sex-related differences in the pressure diuresis/natriuresis relationships in anaesthetized, renally denervated rabbits, using an extracorporeal circuit to perfuse the left kidney with the rabbit's own blood, through a series of step-wise increases in renal artery pressure (RAP) (from 65 to 130 mmHg). Urine flow, sodium excretion, and the fractional excretions of sodium and urine increased with increasing RAP, and were greater in male than in female rabbits at all levels of RAP-tested. However, these apparent sex-related differences in the acute pressure diuresis/natriuresis relationships were not reflected in alterations in chronic regulation of mean arterial pressure (MAP). Thus, in rabbits on a normal salt diet (0.85 g day(-1)), resting conscious MAP was significantly greater in males (87 +/- 3 mmHg) compared with females (77+/-1 mmHg). Chronically increasing daily salt intake to 4.98 g day(-1) for 28 days had no significant effect on resting conscious MAP in either sex. Thus, although our observations indicate sex differences, at least under the present experimental conditions, in the factors regulating extracellular fluid volume, these do not appear to have a major impact in setting the level of MAP in the long term.

The time course of the renal blood flow and GFR responses to narrowing of the renal artery in conscious dogs is reviewed. The initial response to this threat to renal perfusion is renal vasodilatation, but within minutes a secondary vasoconstriction mediated by angiotensin II begins to develop. Angiotensin II-mediated contraction of mesangial cells is also demonstrable, but this does not apparently reduce the filtration surface area of the glomerular capillaries. The intrarenal effects of angiotensin II restore GFR back to normal within one to two weeks, by which time circulating plasma angiotensin II levels are no longer elevated. In contrast to its effects on GFR, angiotensin II has minimal effects on renal blood flow after stenosis. This may be because, (i) blood flow is mainly determined by the hydraulic resistance of the stenosis; (ii) renal vasoconstriction has relatively little effect on flow due to the particular hemodynamic properties of the stenoses, and (iii) a major site of action of angiotensin II may be within the glomerulus. Thus angiotensin II has a homeostatic role in the maintenance of GFR during renal artery narrowing and one component of this role may involve mesangial contraction.

1. Renal cellophane wrapping to produce hypertension causes thickening of the capsule of the kidney. To determine whether this compresses the kidney, deep renal vein wedge pressure was measured as an estimate of tissue pressure in anaesthetized rabbits 1 month after cellophane wrapping (n = 5) or a sham operation (n = 3). 2. Renal vein wedge pressure was 18.3 +/- 2.0 mmHg in hypertensive rabbits and 8.4 +/- 1.1 mmHg in the sham-operated rabbits. 3. Arterial pressure was raised or lowered with angiotensin II or glyceryl trinitrate, respectively. Arterial and wedge pressures were approximately linearly related and, at any given arterial pressure, wedge pressure was approximately 8 mmHg higher in the cellophane-wrapped kidney than in the kidney of the sham-operated group. 4. These results, showing that renal wedge pressure is elevated in renal wrap rabbits, indicate that the kidneys are compressed, probably by the thickened renal capsule. This may explain the increased renal vascular resistance seen in this form of hypertension.