Soluble (Pro)Renin Receptor Levels Are Regulated by Plasma Renin Activity and Correlated with Edema in Mice and Humans with HFrEF

Abstract

Symptomatic heart failure with reduced ejection fraction (HFrEF) is characterized by edema and chronic pathological activation of the classical renin-angiotensin-aldosterone system (RAAS). The soluble (pro)renin receptor (s(P)RR) is released into circulation by proteolytic cleavage of tissue expressed (P)RR and is a candidate biomarker of RAAS activation. However, previous studies linked elevated levels of s(P)RR in patients with HFrEF to renal dysfunction. Utilizing prospectively enrolled patients with comparable rEF, we show that increased plasma levels of s(P)RR are associated with symptomatic HF (characterized by edema), independent of chronic renal dysfunction. We also found that s(P)RR levels were positively correlated with patient plasma renin activity (PRA). Normotensive mice with dilated cardiomyopathy (DCM) and HFrEF, without renal dysfunction, showed plasma s(P)RR and PRA patterns similar to human HFrEF patients. Plasma s(P)RR levels positively correlated with PRA and systemic edema, but not with EF, resembling findings in patients with HFrEF without chronic kidney dysfunction. In female DCM mice with elevated PRA levels and plasma s(P)RR levels, a randomized, blinded trial comparing the direct renin inhibitor, aliskiren vs. vehicle control, showed that direct renin inhibition normalized PRA, lowered s(P)RR, and prevented symptomatic HFrEF. Considered in light of previous findings, these data suggest that, in HFrEF, in the absence of renal dysfunction, elevation of plasma s(P)RR levels is caused by increased PRA and associated with the development of systemic edema.

Keywords: HFrEF; edema; renin plasma activity; soluble (pro)renin receptor.

Figure 1

Plasma renin activity (PRA) [18] (a) and soluble (pro)renin receptor, s(P)RR (b) levels alteration in clinical DCM and symptomatic HFrEF. (c) Spearman correlation of PRA vs. s(P)RR. Arbitrary units (AU). Comparisons between groups were analyzed with Mann–Whitney multiple comparison; * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001. Black: healthy—no HF and normal EF; Blue: DCM (dilated cardiomyopathy)—pre-symptomatic HFrEF; Red: DCM + sHF (HF symptoms)—symptomatic HFrEF.

Figure 2

Schematic presentation of established progressive mouse model of dilated cardiomyopathy heart failure with reduced ejection fraction (DCM-HFrEF).

Figure 3

Levels of plasma renin activity (PRA) and soluble (pro)renin receptor (s(P)RR in male and female control mice vs. DCM mice with stage D heart failure: (a) levels of PRA; (b) plasma levels of (s(P)RR; (c) Spearman correlation analysis of combined s(P)RR (c) vs. combined PRA. Groups represent female mice with DCM (13 weeks of age, corresponding stage D HF, DCM + HF) and congenic wild-type (WT) mice at 13 weeks of age, and male mice with DCM (20 weeks of age corresponding to stage D HF) and congenic WT at 20 weeks of age. Arbitrary units (AU). Data were analyzed with two-way ANOVA with Tukey’s multiple comparison; * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001; ns—not significant. HF—heart failure; DCM—dilated cardiomyopathy.

Figure 4

Plasma soluble (pro)renin receptor (s(P)RR) levels are correlated with plasma renin activity (PRA) and edema and suppressed by direct inhibition of renin activity in mice with DCM. (a) Experimental design: female mice with DCM (7 weeks of age corresponding stage B HF) were randomly assigned to treatment with direct renin inhibitor (DRI) aliskiren (DRI) in drinking water or vehicle (control, plain drinking water). PRA [40] (b) and s(P)RR (c) level alterations in mice with DCM at 13 weeks of age after treatment with vehicle (control) or DRI. Arbitrary units (AU). Data were analyzed with one-way ANOVA with Tukey’s multiple comparison. (d) Spearman correlation analysis of s(P)RR (b) vs. PRA (a). The values for the wildtype (WT, n = 4 or 7) are shown as a black dotted line for reference. Association of s(P)RR plasma levels with systemic edema assessed by ECW (e) or EF (f) by Pearson’s correlation analysis. QMR—quantitative magnetic resonance for the extracellular water retention (ECW) monitoring; EF—ejection fraction. Data are presented as the mean ± SE; * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001 for control vs. DRI; ⁺⁺ p < 0.01 and ⁺⁺⁺⁺ p < 0.0001 for control vs. WT; ns—not significant.

Figure 5

Simplified schematic summary. Levels of PRA, s(P)RR, and edema increase in worsening dilated cardiomyopathy (DCM) with HF without renal impairment. Levels of PRA and s(P)RR are closely correlated. Increased PRA activates the RAAS to enhance edema formation and worsen DCM. Normalization of PRA level with a direct renin inhibitor (DRI) suppresses s(P)RR, edema, and progression of cardiomyopathy to HFrEF. Increased levels of s(P)RR may worsen DCM and promote edema through direct effects or through indirect effects, by increasing PRA. In HFrEF without chronic kidney disease, the protective effects of DRI may be mediated in part through suppression of s(P)RR.