Potential of soluble (pro)renin receptor in kidney disease: can it go beyond a biomarker?

(Pro)renin receptor (PRR), also termed ATPase H-transporting accessory protein 2 (ATP6AP2), is a type I transmembrane receptor and is capable of binding and activating prorenin and renin. Apart from its association with the renin-angiotensin system, PRR has been implicated in diverse developmental, physiological, and pathophysiological processes. Within the kidney, PRR is predominantly expressed in the distal nephron, particularly the intercalated cells, and activation of renal PRR contributes to renal injury in various rodent models of chronic kidney disease.

Soluble (Pro)Renin Receptor in Hypertension.

The (pro)renin receptor (PRR) was originally cloned as a specific single-transmembrane receptor for prorenin and renin and has now emerged as a multifunctional protein implicated in a wide variety of developmental and physiopathological processes. Activation of PRR in the kidney causes Na+ and water retention, contributing to elevation of blood pressure in response to various hypertensive stimuli. Part of the renal action of PRR depends on activation of intrarenal renin-angiotensin system.

2022 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty.

Objective: To develop updated American College of Rheumatology/American Association of Hip and Knee Surgeons guidelines for the perioperative management of disease-modifying medications for patients with rheumatic diseases, specifically those with inflammatory arthritis (IA) and those with systemic lupus erythematosus (SLE), undergoing elective total hip arthroplasty (THA) or elective total knee arthroplasty (TKA).

Methods: We convened a panel of rheumatologists, orthopedic surgeons, and infectious disease specialists, updated the systematic literature review, and included currently available medications for the clinically relevant population, intervention, comparator, and outcomes (PICO) questions. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence and the strength of recommendations using a group consensus process.

2022 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty.

Objective: To develop updated guidelines for the perioperative management of disease-modifying medications for patients with rheumatic diseases, specifically those with inflammatory arthritis (IA) and those with systemic lupus erythematosus (SLE), undergoing elective total hip arthroplasty (THA) or elective total knee arthroplasty (TKA).

Methods: We convened a panel of rheumatologists, orthopedic surgeons, and infectious disease specialists, updated the systematic literature review, and included currently available medications for the clinically relevant population, intervention, comparator, and outcomes (PICO) questions. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence and the strength of recommendations using a group consensus process.

2022 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty.

Objective: To develop updated guidelines for the perioperative management of disease-modifying medications for patients with rheumatic diseases, specifically those with inflammatory arthritis (IA) and those with systemic lupus erythematosus (SLE), undergoing elective total hip arthroplasty (THA) or elective total knee arthroplasty (TKA).

Methods: We convened a panel of rheumatologists, orthopedic surgeons, and infectious disease specialists, updated the systematic literature review, and included currently available medications for the clinically relevant population, intervention, comparator, and outcomes (PICO) questions. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence and the strength of recommendations using a group consensus process.

Revisiting the relationship between (Pro)Renin receptor and the intrarenal RAS: focus on the soluble receptor.

Purpose Of Review: The (pro)renin receptor (PRR), also termed as ATPase H+ transporting accessory protein 2 (ATP6AP2), was originally cloned as a specific receptor for prorenin and renin [together called (pro)renin]. Given the wide tissue distribution of PRR, PRR was further postulated to act as a regulator of tissue renin. However, assigning a physiological role of PRR within the renin-angiotensin system (RAS) has been challenging largely due to its pleotropic functions in regulation of embryogenesis, autophagy, and H+ transport.

Na-Retaining Action of COX-2 (Cyclooxygenase-2)/EP Pathway in the Collecting Duct via Activation of Intrarenal Renin-Angiotensin-Aldosterone System and Epithelial Sodium Channel.

Background: The collecting duct (CD) is a major site of both biosynthesis and action of prostaglandin E as highlighted by the predominant expression of COX-2 (cyclooxygenase-2) and some E-prostanoid (EP) subtypes at this nephron site. The purpose of this study was to determine the relevance and mechanism of CD COX-2/prostaglandin E/EP signaling for the regulation of Na hemostasis during Na depletion.

Methods: Mice with Aqp2Cre-driven deletion of COX-2 (COX-2Aqp2Cre) or the EP subtype (EPAqp2Cre) were generated and the Na-wasting phenotype of these mice during low-salt (LS) intake was examined.

(Pro)renin Receptor Regulates Phosphate Homeostasis in Rats Releasing Fibroblast Growth Factor-23.

Phosphate (Pi) is one of the basic necessities required for sustenance of life and its metabolism largely relies on excretory function of the kidney, a process chiefly under the endocrine control of bone-derived fibroblast growth factor 23 (FGF23). However, knowledge gap exists in understanding the regulatory loop responsible for eliciting phophaturic response to Pi treatment. Here, we reported a novel role of (pro)renin receptor (PRR) in mediating phosphaturic response to Pi treatment upregulation of FGF23 production.

Soluble (Pro)Renin Receptor as a Negative Regulator of NCC (Na-Cl Cotransporter) Activity.

[Figure: see text].

(Pro)renin receptor antagonist PRO20 attenuates nephrectomy-induced nephropathy in rats via inhibition of intrarenal RAS and Wnt/β-catenin signaling.

Introduction: (Pro)renin receptor has emerged as a new member of the renin-angiotensin system implicated in the pathogenesis of chronic kidney disease (CKD). Herein we report characterization of the therapeutic potential of (pro)renin receptor (PRR) antagonist PRO20 in 5/6 nephrectomy (5/6Nx) rats.

Methods: Male Wistar rats underwent 5/6Nx followed by treatment with vehicle or received daily injections of a PRR inhibitor PRO20 (700 μg/kg) via the 3 s.

Mutagenesis of the Cleavage Site of Pro Renin Receptor Abrogates Angiotensin II-Induced Hypertension in Mice.

[Figure: see text].

Diuretic Action of Apelin-13 Mediated by Inhibiting cAMP/PKA/sPRR Pathway.

Emerging evidence is showing that apelin plays an important role in regulating salt and water balance by counteracting the antidiuretic action of vasopressin (AVP). However, the underlying mechanism remains unknown. Here, we hypothesized that (pro) renin receptor (PRR)/soluble prorenin receptor (sPRR) might mediate the diuretic action of apelin in the distal nephron.

Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor.

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II)-dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation.

Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II-Induced Hypertension in Mice.

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry.

The interaction partners of (pro)renin receptor in the distal nephron.

The (pro)renin receptor (PRR), a key regulator of intrarenal renin-angiotensin system (RAS), is predominantly presented in podocytes, proximal tubules, distal convoluted tubules, and the apical membrane of collecting duct A-type intercalated cells, and plays a crucial role in hypertension, cardiovascular disease, kidney disease, and fluid homeostasis. In addition to its well-known renin-regulatory function, increasing evidence suggests PRR can also act in a variety of intracellular signaling cascades independently of RAS in the renal medulla, including Wnt/β-catenin signaling, cyclooxygenase-2 (COX-2)/prostaglandin E (PGE ) signaling, and the apelinergic system, and work as a component of the vacuolar H -ATPase. PRR and these pathways regulate the expression/activity of each other that controlling blood pressure and renal functions.

Soluble (pro)renin receptor promotes the fibrotic response in renal proximal tubule epithelial cells in vitro via the Akt/β-catenin/Snail signaling pathway.

Tubulointerstitial fibrosis has been regarded as a critical event in the pathogenesis of chronic kidney disease. The soluble form of (pro)renin receptor (sPRR), generated by site-1 protease (S1P) cleavage of full-length PRR, can be detected in biological fluid and elevated under certain pathological conditions. The present study was designed to evaluate the potential role of sPRR in the regulation of the fibrotic response in a cultured human renal proximal tubular cell line (HK-2 cells) in the setting of transforming growth factor (TGF)-β or sPRR-His treatment.

(Pro)renin receptor decoy peptide PRO20 protects against adriamycin-induced nephropathy by targeting the intrarenal renin-angiotensin system.

Adriamycin (ADR) administration in susceptible rodents such as the BALB/c mouse strain produces injury to the glomerulus mimicking human chronic kidney disease due to primary focal segmental glomerulosclerosis. The goal of the present study was to use this model to investigate antiproteinuric actions of the (pro)renin receptor decoy inhibitor PRO20. BALB/c mice were pretreated for 1 day with PRO20 at 500 μg·kg·day via an osmotic minipump followed by a single injection of vehicle or ADR (10 mg/kg) via the tail vein.

COX-2-independent activation of renal (pro)renin receptor contributes to DOCA-salt hypertension in rats.

It has been shown that cyclooxygenase (COX)-2-dependent activation of renal (pro)renin receptor (PRR) contributes to angiotensin II (ANG II)-induced hypertension. However, less is known about the involvement of this mechanism in ANG II-independent hypertension. The goal of the present study was to test whether or not COX-2-dependent upregulation of PRR serves as a universal mechanism contributing to ANG II-dependent and -independent hypertension.

The Elabela in hypertension, cardiovascular disease, renal disease, and preeclampsia: an update.

: Although considerable success has been shown for antihypertensive medications, the resistant hypertension and hypertension-related organ damages are still the important clinical issues and pose as high health and economic pressure. Therefore, novel therapeutic techniques and antihypertensive drugs are needed to advance more effective therapy of hypertension and hypertension-related disease to ameliorate mortality and healthcare costs worldwide. In this review, we highlight the latest progress in supporting the therapeutic potential of Elabela (ELA), a recently discovered early endogenous ligand for G-protein-coupled receptor apelin peptide jejunum, apelin receptor.

Soluble (pro)renin receptor treats metabolic syndrome in mice with diet-induced obesity via interaction with PPARγ.

The therapies available for management of obesity and associated conditions are limited, because they are often directed toward an individual component of metabolic syndrome and are associated with adverse effects. Here, we report the multifaceted therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed sPRR-His, in a mouse model of diet-induced obesity (DIO). In the DIO model, 2-week administration of sPRR-His lowered body weight and remarkably improved multiple metabolic parameters in the absence of fluid retention.

ELABELA antagonizes intrarenal renin-angiotensin system to lower blood pressure and protects against renal injury.

Emerging evidence has demonstrated that (pro)renin receptor (PRR)-mediated activation of intrarenal renin-angiotensin system (RAS) plays an essential role in renal handling of Na and water balance and blood pressure. The present study tested the possibility that the intrarenal RAS served as a molecular target for the protective action of ELABELA (ELA), a novel endogenous ligand of apelin receptor, in the distal nephron. By RNAscope and immunofluorescence, mRNA and protein expression of endogenous ELA was consistently localized to the collecting duct (CD).

Soluble (pro)renin receptor regulation of ENaC involved in aldosterone signaling in cultured collecting duct cells.

We have previously shown that activation of (pro)renin receptor (PRR) induces epithelial Na channel (ENaC) activity in cultured collecting duct cells. Here, we examined the role of soluble PRR (sPRR), the cleavage product of PRR in ENaC regulation, and further tested its relevance to aldosterone signaling. In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM within minutes induced a significant and transient increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique.

Site-1 protease-derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capability.

The antidiuretic hormone vasopressin (AVP), acting through its type 2 receptor (V2R) in the collecting duct (CD), critically controls urine concentrating capability. Here, we report that site-1 protease-derived (S1P-derived) soluble (pro)renin receptor (sPRR) participates in regulation of fluid homeostasis via targeting V2R. In cultured inner medullary collecting duct (IMCD) cells, AVP-induced V2R expression was blunted by a PRR antagonist, PRO20; a PRR-neutralizing antibody; or a S1P inhibitor, PF-429242.

Protein Compositions Changes of Circulating Microparticles in Patients With Valvular Heart Disease Subjected to Cardiac Surgery Contribute to Systemic Inflammatory Response and Disorder of Coagulation.

We recently demonstrated that circulating microparticles (MPs) from patients with valvular heart diseases (VHD) subjected to cardiac surgery impaired endothelial function and vasodilation. However, it is unknown whether or not the protein composition of these circulating MPs actually changes in response to the disease and the surgery. Circulating MPs were isolated from age-matched control subjects (n = 50) and patients (n = 50) with VHD before and 72 h after cardiac surgery.