Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Abstract

T he (pro)renin receptor [(P)RR] has been implicated as a receptor for renin/prorenin (denoted as [pro]renin)-stimulated signaling, and plays a role in local renin-angiotensin system activation by nonproteolytically activating bound prorenin. 1 In experimental assays (pro)renin-(P)RR signaling results in extracellular signal-regulated kinase 1/2 (Erk1/2) activation, and as a consequence upregulation of profibrotic factors, such as transforming growth factor β, collagen, and fibronectin. [2][3][4][5][6] However, the physiological relevance of the (pro)renin-(P)RR interaction is questionable because the (pro)renin concentrations required are >1000× higher than observed under (patho) physiological conditions. 7,8 Recently, (pro)renin-independent functions for (P)RR have been reported, including a function as an accessory protein of the vacuolar H + -ATPase (V-ATPase). 9 V-ATPases are multisubunit complexes, and they are expressed virtually in all cells types. They play an important role in protein trafficking, receptor recycling, and lysosomal degradation by acidifying intracellular compartments.10,11 Depletion of the (P)RR results in decreased protein levels of V-ATPase subunits, impaired acidification of intracellular compartments, and defects in autophagy.12-14 V-ATPases are also found at the plasma membrane in certain cell types, such as intercalated cells of the collecting duct. Accordingly, we previously reported that the (P)RR is required for both prorenin-dependent and proreninindependent regulation of V-ATPase activity in collecting duct cells.15 The (P)RR has been also recently implicated in canonical Wnt and PCP signaling, [16][17][18] emphasizing the notion that our understanding of (P)RR function remains incomplete. In This Issue, see p 183Editorial, see p 187To address this, we used an unbiased proteomics approach to discover potential novel functions of the (P)RR. We mapped the (P)RR-interactome and identified sortilin 1 (SORT1) as Objective: To uncover renin-angiotensin system-independent functions of the (P)RR. Methods and Results: We used a proteomics-based approach to purify and identify (P)RR-interacting proteins.This resulted in identification of sortilin-1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (

Effects of Direct Renin Blockade on Renal & Systemic Hemodynamics and on RAAS Activity, in Weight Excess and Hypertension: A Randomized Clinical Trial

“…However, the binding affinity of this receptor for renin and its precursor prorenin was found to be in the nanomolar range, while their in-vivo levels are many orders below this range, even during DRI treatment [43, 44]. On this basis, combined with the fact that the (pro)renin receptor is now additionally known to be an accessory subunit of vacuolar H + -ATPase, displaying multiple effects that are entirely unrelated to renin and/or prorenin, e.g., with regard to cardiomyocyte autophagy [45], polyuria and renal acid-base regulation [46], and LDL metabolism [47], this idea is now being abandoned [48]. …”

Do prorenin-synthesizing cells release active, ‘open’ prorenin?

“…The discovery of the (pro)renin receptor [8] caused a lot of excitement, but recent studies have revealed that its in-vivo function in reality is largely, if not entirely, proreninindependent [25][26][27]. The discovery of the (pro)renin receptor [8] caused a lot of excitement, but recent studies have revealed that its in-vivo function in reality is largely, if not entirely, proreninindependent [25][26][27].…”

Maximum renal responses to renin inhibition in healthy study participants

“…However, recent studies questioned the physiological relevance of these findings, since in reality, prorenin concentrations are many orders of magnitude below the levels that are required to interact with this receptor, even during treatment with RAS blockers [38]. Indeed, the (pro)renin receptor has now also been linked to functions beyond the RAS [39]. To what degree its concentrations vary in relation with salt intake still needs to be investigated further.…”