Importance of the (Pro)renin Receptor in Activating the Renin-Angiotensin System During Normotensive and Preeclamptic Pregnancies

Abstract

Purpose of review: For a healthy pregnancy to occur, a controlled interplay between the maternal circulating renin-angiotensin-aldosterone system (RAAS), placental renin-angiotensin system (RAS) and intrarenal renin-angiotensin system (iRAS) is necessary. Functionally, both the RAAS and iRAS interact to maintain blood pressure and cardiac output, as well as fluid and electrolyte balance. The placental RAS is important for placental development while also influencing the maternal circulating RAAS and iRAS. This narrative review concentrates on the (pro)renin receptor ((P)RR) and its soluble form (s(P)RR) in the context of the hypertensive pregnancy pathology, preeclampsia.

Recent findings: The (P)RR and the s(P)RR have become of particular interest as not only can they activate prorenin and renin, thus influencing levels of angiotensin II (Ang II), but s(P)RR has now been shown to directly interact with and stimulate the Angiotensin II type 1 receptor (AT₁R). Levels of both placental (P)RR and maternal circulating s(P)RR are elevated in patients with preeclampsia. Furthermore, s(P)RR has been shown to increase blood pressure in non-pregnant and pregnant rats and mice. In preeclamptic pregnancies, which are characterised by maternal hypertension and impaired placental development and function, we propose that there is enhanced secretion of s(P)RR from the placenta into the maternal circulation. Due to its ability to both activate prorenin and act as an AT₁R agonist, excess maternal circulating s(P)RR can act on both the maternal vasculature, and the kidney, leading to RAS over-activation. This results in dysregulation of the maternal circulating RAAS and overactivation of the iRAS, contributing to maternal hypertension, renal damage, and secondary changes to neurohumoral regulation of fluid and electrolyte balance, ultimately contributing to the pathophysiology of preeclampsia.

Keywords: (Pro)renin Receptor ((P)RR); Preeclampsia; Renin Angiotensin System (RAS).

Fig. 1

Diagnostic criteria of preeclampsia. Preeclampsia is clinically diagnosed when patients present with new-onset hypertension and one, or more, of the following symptoms: renal involvement (including significant proteinuria (urine protein/creatinine ≥ 30mg/mmol)), haematological, liver or neurological involvement, pulmonary oedema and/or fetal growth restriction (FGR) [7]. Created with BioRender.com

Fig. 2

Renin-angiotensin system (RAS) signalling. Renin, or prorenin activated by binding to the (pro)renin receptor ((P)RR), can cleave angiotensin I (Ang I) from angiotensinogen (AGT). Ang I is then converted to Ang II by angiotensin-converting enzyme (ACE). Ang II can either directly activate the Ang II type 1 (AT₁R) or type II (AT₂R) receptor. Created with BioRender.com

Fig. 3

The agonistic effects of soluble (pro)renin receptor (s(P)RR) on the renin-angiotensin system (RAS). The soluble prorenin receptor (s(P)RR), can bind prorenin and enhance its enzymatic activity through non-proteolytic conformational change. Prorenin can then cleave angiotensin I (Ang I) from angiotensinogen (AGT) and initiate RAS signalling. The s(P)RR can also act as a direct agonist for the Ang II type 1 receptor (AT₁R). AT₁R activation results in hypertension and endothelial dysfunction, the two main symptoms of preeclampsia. Red arrows indicate increased activity/expression and blue arrows represent decreased activity/expression. Created with BioRender.com