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.

Falling corin and ANP activity levels accelerate development of heart failure and cardiac fibrosis

“…Declines in corin levels indicate systolic dysfunction as it happened even before the increases in plasma ANP and BNP levels and the onset of edema ( 21 , 23 , 26 , 30 ), which is a major hallmark of HF and a key driver of symptoms ( 3 , 47 ). Consequently, as the natriuretic peptide system is impaired and becomes insufficient to properly balance RAAS activity, pathologically active RAAS further promotes cardiac dilation, fibrotic ventricular remodeling, salt-water retention (edema), and HFrEF development in humans and pre-clinical models ( 4 , 6 , 40 , 42 , 44 , 46 , 48 , 49 ). Although HFrEF (stages C-D) is associated with a boost of pro-ANP expression by the ventricle's cardiomyocytes ( 21 , 37 ), pro-ANP cleavage and production of biologically active ANP are compromised as the level of corin is significantly reduced ( 21 ).…”

“…As DCM progresses to HFrEF (stages C-D), renin is over-secreted by the kidneys into circulation. It triggers Ang II activation pathways (systemic and locally within the heart), cardiac Ang II-independent signaling and stimulates aldosterone secretion from the adrenal glands, which fosters fibrotic remodeling ( 6 , 40 , 43 , 49 , 50 ). Systemic (circulating) Ang II and aldosterone play an important role in cardiac fibrosis development, as increased local production of Ang II in the heart is not enough to induce ventricular hypertrophy or fibrosis ( 51 ).…”