Review

Authors: Frank Schweda, Ulla Friis, Charlotte Wagner...

The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in salt, volume, and blood pressure homeostasis of the body. Renin is mainly produced and released into circulation by the so-called juxtaglomerular epithelioid cells, located in the walls of renal afferent arterioles at the entrance of the glomerular capillary network. It has been known for a long time that renin synthesis and secretion are stimulated by the sympathetic nerves and the prostaglandins and are inhibited in negative feedback loops by angiotensin II, high blood pressure, salt, and volume overload. In contrast, the events controlling the function of renin-secreting cells at the organ and cellular level are markedly less clear and remain mysterious in certain aspects. The unravelling of these mysteries has led to new and interesting insights into the process of renin release.

Topics: Animals; Cyclic AMP; Humans; Juxtaglomerular Apparatus; Kidney; Paracrine Communication; Protein Processing, Post-Translational; Renin; Secretory Vesicles; Signal Transduction

PubMed: 17928544
DOI: 10.1152/physiol.00024.2007

Authors: Torbjörn Almgren, Narmin Bigdeli, Augustinas Sakinis...

Reninoma - rare juxtaglomerular tumor associated with hypertension We present a case study of two female patients, aged 20-30 years, who were diagnosed with reninoma, a rare juxtaglomerular tumor associated with hypertension, high plasma renin and hypokalemia. Both patients were referred to the Department of Internal Medicine at Sahlgrenska University Hospital, but their cases were ten years apart. In both instances, the renin-secreting tumor was surgically removed, resulting in the normalization of blood pressure without the need for antihypertensive medication. Based on our findings, we recommend physicians interested in hypertension to analyze plasma renin levels before starting antihypertensive treatment in young patients. Additionally, we suggest performing an MRI of the kidneys followed by renal vein catheterization, which can confirm but not exclude the presence of a reninoma. It is important to note that treatment with RAAS (renin-angiotensin-aldosterone system) blockers may mask the effects of reninoma on blood pressure and potassium levels. Since RAAS blockers are contraindicated during pregnancy, it is of particular importance to diagnose reninoma in young women of childbearing age.

Topics: Humans; Female; Renin; Antihypertensive Agents; Hypertension; Kidney Neoplasms; Renin-Angiotensin System; Adenoma

PubMed: 38054585
DOI: No ID Found

Authors: Rudy M Ortiz, Ryousuke Satou, Jia L Zhuo...

It has been our pleasure to have been able to develop two special issues within the International Journal of Molecular Sciences: Renin-Angiotensin-Aldosterone System in Pathologies and Renin-Angiotensin-Aldosterone System in Metabolism & Disease [...].

Topics: Humans; Renin-Angiotensin System; Metabolic Diseases; Aldosterone; Renin; Angiotensin II

PubMed: 37108577
DOI: 10.3390/ijms24087413

Review

Authors: R Ariel Gomez, Brian Belyea, Silvia Medrano...

Renin-expressing cells appear early in the embryo and are distributed broadly throughout the body as organogenesis ensues. Their appearance in the metanephric kidney is a relatively late event in comparison with other organs such as the fetal adrenal gland. The functions of renin cells in extra renal tissues remain to be investigated. In the kidney, they participate locally in the assembly and branching of the renal arterial tree and later in the endocrine control of blood pressure and fluid-electrolyte homeostasis. Interestingly, this endocrine function is accomplished by the remarkable plasticity of renin cell descendants along the kidney arterioles and glomeruli which are capable of reacquiring the renin phenotype in response to physiological demands, increasing circulating renin and maintaining homeostasis. Given that renin cells are sensors of the status of the extracellular fluid and perfusion pressure, several signaling mechanisms (β-adrenergic receptors, Notch pathway, gap junctions and the renal baroreceptor) must be coordinated to ensure the maintenance of renin phenotype--and ultimately the availability of renin--during basal conditions and in response to homeostatic threats. Notably, key transcriptional (Creb/CBP/p300, RBP-J) and posttranscriptional (miR-330, miR125b-5p) effectors of those signaling pathways are prominent in the regulation of renin cell identity. The next challenge, it seems, would be to understand how those factors coordinate their efforts to control the endocrine and contractile phenotypes of the myoepithelioid granulated renin-expressing cell.

Topics: Animals; Humans; Kidney; Organogenesis; Renin; Stem Cells

PubMed: 24337407
DOI: 10.1007/s00467-013-2688-0

Review

Authors: Tianxin Yang

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. In recent years, accumulating evidence suggests that the prohypertensive action of renal PRR was largely mediated by production of the 28-kDa soluble (pro)renin receptor through protease-mediated cleavage of the extracellular domain of PRR. The generation of multiple isoforms of PRR due to the protease-mediated cleavage partially explains diversified actions of PRR. The current review will summarize recent advances in understanding the roles of sPPR in animal models of hypertension.

Topics: Animals; Prorenin Receptor; Receptors, Cell Surface; Hypertension; Kidney; Renin-Angiotensin System; Renin

PubMed: 35871512
DOI: 10.1159/000525635

Review

Authors: Undurti N Das, Ahmet Hacimüftüoglu, Erol Akpinar...

Renin plays a significant role in the regulation of blood pressure and fluid volume by modulating the renin‒angiotensin‒aldosterone (RAAS) system. Renin suppression reduces serum aldosterone levels and lowers blood pressure in addition to preserving renal function. However, exactly how renin synthesis and action are regulated and how renin suppression preserves renal function are not clear. We propose that arachidonic acid (AA) and its metabolites control renin synthesis, secretion, and action by virtue of its (AA) anti-inflammatory, cytoprotective actions and ability to regulate the secretion of renin. These findings suggest that direct renin suppression results in changes in AA metabolism. This proposal implies that AA and its metabolites may be developed as potential drugs to prevent and manage hypertension and preserve renal function.

Topics: Arachidonic Acid; Humans; Renin; Renin-Angiotensin System; Animals; Aldosterone; Hypertension; Kidney; Blood Pressure

PubMed: 39962508
DOI: 10.1186/s12944-025-02463-3

Authors: Joseph C Maggiore, Ryan LeGraw, Aneta Przepiorski...

Vascularization plays a critical role in organ maturation and cell-type development. Drug discovery, organ mimicry, and ultimately transplantation hinge on achieving robust vascularization of in vitro engineered organs. Here, focusing on human kidney organoids, we overcame this hurdle by combining a human induced pluripotent stem cell (iPSC) line containing an inducible ETS translocation variant 2 (ETV2) (a transcription factor playing a role in endothelial cell development) that directs endothelial differentiation in vitro, with a non-transgenic iPSC line in suspension organoid culture. The resulting human kidney organoids show extensive endothelialization with a cellular identity most closely related to human kidney endothelia. Endothelialized kidney organoids also show increased maturation of nephron structures, an associated fenestrated endothelium with de novo formation of glomerular and venous subtypes, and the emergence of drug-responsive renin expressing cells. The creation of an engineered vascular niche capable of improving kidney organoid maturation and cell type complexity is a significant step forward in the path to clinical translation. Thus, incorporation of an engineered endothelial niche into a previously published kidney organoid protocol allowed the orthogonal differentiation of endothelial and parenchymal cell types, demonstrating the potential for applicability to other basic and translational organoid studies.

Topics: Humans; Organoids; Renin; Induced Pluripotent Stem Cells; Cell Differentiation; Endothelial Cells; Kidney; Transcription Factors; Neovascularization, Physiologic; Cell Lineage; Cell Line

PubMed: 38901605
DOI: 10.1016/j.kint.2024.05.026

Authors: Yuzhou Zhang, Bertha Martin, M Ashley Spies...

Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 °C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.

Topics: Humans; Amides; Atypical Hemolytic Uremic Syndrome; Complement Activation; Complement C3; Complement C3-C5 Convertases; Complement Pathway, Alternative; Fumarates; Kidney Diseases; Renin

PubMed: 38008161
DOI: 10.1016/j.kint.2023.11.005

Review

Authors: Nicolas F Schroten, Carlo A J M Gaillard, Dirk J van Veldhuisen...

The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure-associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1-7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways.

Topics: Amides; Antihypertensive Agents; Cardio-Renal Syndrome; Fumarates; Heart Failure; Humans; Renin; Renin-Angiotensin System

PubMed: 21695549
DOI: 10.1007/s10741-011-9262-2

Review

Authors: Hiroki Yamaguchi, R Ariel Gomez, Maria Luisa S Sequeira-Lopez...

During embryonic and neonatal life, renin cells contribute to the assembly and branching of the intrarenal arterial tree. During kidney arteriolar development renin cells are widely distributed throughout the renal vasculature. As the arterioles mature, renin cells differentiate into smooth muscle cells, pericytes, and mesangial cells. In adult life, renin cells are confined to the tips of the renal arterioles, thus their name juxtaglomerular cells. Juxtaglomerular cells are sensors that release renin to control blood pressure and fluid-electrolyte homeostasis. Three major mechanisms control renin release: (1) β-adrenergic stimulation, (2) macula densa signaling, and (3) the renin baroreceptor, whereby a decrease in arterial pressure leads to increased renin release whereas an increase in pressure results in decrease renin release. Cells from the renin lineage exhibit plasticity in response to hypotension or hypovolemia, whereas relentless, chronic stimulation induces concentric arterial and arteriolar hypertrophy, leading to focal renal ischemia. The renin cell baroreceptor is a nuclear mechanotransducer within the renin cell that transmits external forces to the chromatin to regulate gene expression. In addition to mechanotransduction, the pressure sensor of the renin cell may enlist additional molecules and structures including soluble signals and membrane proteins such as gap junctions and ion channels. How these various components integrate their actions to deliver the exact amounts of renin to meet the organism needs is unknown. This review describes the nature and origins of renin cells, their role in kidney vascular development and arteriolar diseases, and the current understanding of the blood pressure sensing mechanism.

Topics: Infant, Newborn; Humans; Renin; Blood Pressure; Mechanotransduction, Cellular; Kidney; Hypotension

PubMed: 37313725
DOI: 10.1161/HYPERTENSIONAHA.123.20577