An Emerging Role for Relaxin as a Renal Vasodilator

Abstract

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...

Characterization of a new potent and long-lasting single chain peptide agonist of RXFP1 in cells and in vivo translational models

“…Finally, relaxin also plays an important role in vascular and renal adaptations during gestation 34). The reno-vasodilatory properties of relaxin have been reported in preclinical models 35 , 36 consistent with those described in healthy subjects or heart failure patients 20 . The effect of SA10SC-RLX on renal blood flow in rats is in line with the improvement of renal function by relaxin in patients with heart failure 37 .…”

“…In healthy subjects and heart failure patients, relaxin increases renal plasma flow (RPF) 20 . Thus, we compared the effect of SA10SC-RLX and relaxin on renal blood flow (RBF) in rats to generate translational data.…”

Characterization of a new potent and long-lasting single chain peptide agonist of RXFP1 in cells and in vivo translational models

“…Finally, relaxin also plays an important role in vascular and renal adaptations during gestation (Mc Guane et al 2009). Reno-vasodilatory properties of relaxin have been reported in preclinical models (Danielson et al 1999, Deng et al 2018) consistent with those described in healthy subjects or heart failure patients (Sasser et al 2006). The effect of SA10SC-RLX on renal blood ow in rats is in line with the improvement of renal function by relaxin in patients with heart failure (Unemori et al 2017).…”

“…In healthy subjects and heart failure patients, relaxin increases renal plasma ow (RPF) (Sasser et al 2006). Thus, we compared the effect of SA10SC-RLX and relaxin on renal blood ow (RBF) in rats to generate translational data.…”

R2R01: A long‐acting single‐chain peptide agonist of RXFP1 for renal and cardiovascular diseases

“…Relaxin plays important roles in vascular and renal adaptations during gestation. In healthy subjects and heart failure patients, relaxin increases renal plasma flow (RPF) (Smith et al, 2006) and eGFR (Dahlke et al, 2015) consistent with its renovasodilatory properties reported in preclinical models (Sasser et al, 2006). Deterioration of kidney function is an important prognostic factor for worsening heart failure.…”