(Pro)renin Receptor and LDL Clearance: An Old Player Joins A New Game.
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ABSTRACT:
SUBMITTER: Strong A
PROVIDER: S-EPMC4743896 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
Publications
(Pro)renin Receptor and LDL Clearance: An Old Player Joins A New Game.
Strong Alanna A Musunuru Kiran K
Circulation research 20160101 2
Similar Datasets
Project description:The (pro)renin receptor (PRR) was originally thought to be important in regulating blood pressure via the renin-angiotensin system (RAS), however it is emerging that PRR is instead generally essential for cellular development via its involvement in Wnt signalling. Here, we have specifically deleted PRR from T cells, which require Wnt for their development. T cell-specific PRR-knockout (cKO) mice (ATP6AP2flox/y;Lck-CRE) had a significant decrease in thymic cellularity, corresponding with a 100-fold decrease in the number of CD4+ and CD8+ thymocytes, and a large increase in double negative (DN) precursors. Further characterisation of DN T cell progenitors revealed that deletion of PRR impaired T cell development at multiple stages; including transition from DN3(CD25+CD44-) - DN4(CD25-CD44-), DN4-CD4+ CD8+ double positive (DP), DP-intermediate single positive (CD3-CD8+ ISP) cells. We performed gene expression analysis on sorted DN3 T cells, which indicated that PRR cKO T cells have perturbations in key cellular pathways essential at the DN3 stage, such as RNA processing and translation. Our study identifies a new role for PRR in multiple facets of T cell development, and gives further support to the notion that PRR is generally essential for cellular development.
2015-07-01 | E-MTAB-3568 | biostudies-arrayexpress
Project description:BackgroundLong non-coding RNAs (lncRNAs), which are a portion of non-protein-coding RNAs (ncRNAs), have manifested a paramount role in the pathophysiology of human diseases, particularly in pathogenesis and progression of disease. Myocardial infarction associated transcript (MIAT), which was recently found to demonstrate aberrant expression in various diseases, such as myocardial infarction, schizophrenia, ischemic stroke, diabetic complications, age-related cataract and cancers, is a novel disease-related lncRNA. This work summarize current evidence regarding the biological functions and underlying mechanisms of lncRNA MIAT during disease development.Short conclusionLncRNA MIAT likely represents a feasible cancer biomarker or therapeutic target.
| S-EPMC5851271 | biostudies-literature
Project description:Malaria is caused by a unicellular protozoan pathogen of the genus Plasmodium. Although genes represent monocistronic units that are expressed in a life cycle stage-specific manner, post-transcriptional regulation via translational repression of mRNA has been observed in parasite stages that transition from the vertebrate host to the Anopheles vector. An interesting new type of post-transcriptional control was recently discovered in Plasmodium falciparum stages that infect human erythrocytes. A subgroup of genes that were thought to be transcriptionally silent are actually transcribed but degraded immediately by an RNase II that is recruited to these gene loci. This cryptic RNA is not detectable in steady-state RNA but has been detected using nuclear run-on techniques and in mutant RNase II parasites. Nascent RNA degradation controls virulence genes expressed in a monoallelic fashion and noncoding RNAs (ncRNAs), but also a number of housekeeping-like of genes. More studies on other life cycle stages may reveal the full extent of this type of gene regulation in malaria parasites. It is tempting to speculate that RNase II-mediated gene control may exist in other eukaryotic organisms.
| S-EPMC4615643 | biostudies-other
Project description:The (pro)renin receptor (PRR) is a multifunctional integral membrane protein that serves as a component of the vacuolar H+-ATPase (V-ATPase) and also activates (pro)renin. We recently showed that full-length PRR, found as part of a V-ATPase sub-complex, is abundant in extracellular vesicles shed by osteoclasts. Here, we tested whether these extracellular vesicles stimulate (pro)renin. Extracellular vesicles isolated from the conditioned media of RAW 264.7 osteoclast-like cells or primary osteoclasts were characterized and counted by nanoparticle tracking. Immunoblotting confirmed that full-length PRR was present. Extracellular vesicles from osteoclasts dose-dependently stimulated (pro)renin activity, while extracellular vesicles from 4T1 cancer cells, in which we did not detect PRR, did not activate (pro)renin. To confirm that the ability of extracellular vesicles from osteoclasts to stimulate (pro)renin activity was due to the PRR, the "handle region peptide" from the PRR, a competitive inhibitor of PRR activity, was tested. It dose-dependently blocked the ability of extracellular vesicles to stimulate the enzymatic activity of (pro)renin. In summary, the PRR, an abundant component of extracellular vesicles shed by osteoclasts, stimulates (pro)renin activity. This represents a novel mechanism by which extracellular vesicles can function in intercellular regulation, with direct implications for bone biology.
| S-EPMC8080643 | biostudies-literature
Project description:Most violinists believe that instruments by Stradivari and Guarneri "del Gesu" are tonally superior to other violins--and to new violins in particular. Many mechanical and acoustical factors have been proposed to account for this superiority; however, the fundamental premise of tonal superiority has not yet been properly investigated. Player's judgments about a Stradivari's sound may be biased by the violin's extraordinary monetary value and historical importance, but no studies designed to preclude such biasing factors have yet been published. We asked 21 experienced violinists to compare violins by Stradivari and Guarneri del Gesu with high-quality new instruments. The resulting preferences were based on the violinists' individual experiences of playing the instruments under double-blind conditions in a room with relatively dry acoustics. We found that (i) the most-preferred violin was new; (ii) the least-preferred was by Stradivari; (iii) there was scant correlation between an instrument's age and monetary value and its perceived quality; and (iv) most players seemed unable to tell whether their most-preferred instrument was new or old. These results present a striking challenge to conventional wisdom. Differences in taste among individual players, along with differences in playing qualities among individual instruments, appear more important than any general differences between new and old violins. Rather than searching for the "secret" of Stradivari, future research might best focused on how violinists evaluate instruments, on which specific playing qualities are most important to them, and on how these qualities relate to measurable attributes of the instruments, whether old or new.
| S-EPMC3271912 | biostudies-literature
Project description:The (pro)renin-renin receptor [(P)RR] was discovered as an important novel component of the renin-angiotensin system (RAS). The functional significance of (P)RR is widely studied in renal and vascular pathologies and has sparked interest for a potential role in cardiovascular disease. To investigate the role of (P)RR in cardiac pathophysiology, we aimed to assess (P)RR regulation in adverse cardiac remodelling of the failing heart. In particular, we evaluated the expression of (P)RR in different models of heart failure and across different species. Significantly increased levels of (P)RR mRNA were found in post-myocardial infarcted (MI) hearts of rats (1.6-fold, P < 0.05) and mice (5-fold, P < 0.01), as well as in transgenic rats with overexpression of the mouse renin gene (Ren2) (2.2-fold, P < 0.01). Moreover, we observed a strong increase of (P)RR expression in hearts of dilated cardiomyopathy (DCM) patients (5.3-fold, P < 0.001). Because none of the tested commercially available antibodies appeared to detect endogenous (P)RR, a (P)RR-specific polyclonal antibody was generated to study (P)RR protein levels. (P)RR protein levels were significantly increased in the post-MI rat heart (1.4-fold, P < 0.05) as compared to controls. Most interestingly in DCM patients, a significant 8.7-fold (P < 0.05) increase was observed. Thus, protein expression paralleled gene expression. These results demonstrate that (P)RR expression is strongly up-regulated both in rodent models of heart failure and in the failing human heart, hinting to a potential role for (P)RR in cardiac pathophysiology.
| S-EPMC3822843 | biostudies-literature
Project description:Small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) is a steroid receptor molecular co-chaperone that may substantially influence hormone action and, consequently, hormone-mediated carcinogenesis. To date, published studies describe SGTA as a protein that is potentially critical in a range of biological processes, including viral infection, cell division, mitosis, and cell cycle checkpoint activation. SGTA interacts with the molecular chaperones, heat shock protein 70 (HSP70) and HSP90, and with steroid receptor complexes, including those containing the androgen receptor. Steroid receptors are critical for maintaining cell growth and differentiation in hormonally regulated tissues, such as male and female reproductive tissues, and also play a role in disease states involving these tissues. There is growing evidence that, through its interactions with chaperones and steroid receptors, SGTA may be a key player in the pathogenesis of hormonally influenced disease states, including prostate cancer and polycystic ovary syndrome. Research into the function of SGTA has been conducted in several model organisms and cell types, with these studies showing that SGTA functionality is cell-specific and tissue-specific. However, very few studies have been replicated in multiple cell types or experimental systems. Although a broad range of functions have been attributed to SGTA, there is a serious lack of mechanistic information to describe how SGTA acts. In this review, published evidence linking SGTA with hormonally regulated disease states is summarized and discussed, highlighting the need for future research to more clearly define the biological function(s) of this potentially important co-chaperone.
| S-EPMC7091355 | biostudies-literature
Project description:Background(Pro)renin receptor [(P)RR], a specific receptor for renin and prorenin, was identified as a member of the renin-angiotensin system (RAS). (P)RR is cleaved by furin, and soluble (P)RR [s(P)RR] is secreted into the extracellular space. Previous reports have indicated that plasma s(P)RR levels show a significant positive relationship with urinary protein levels, which represent renal damage. However, it is not fully known whether plasma s(P)RR reflects renal damage.MethodsWe recruited 25 patients who were admitted to our hospital to undergo heminephrectomy. Plasma s(P)RR levels were examined from blood samples drawn before nephrectomy. The extent of renal damage was evaluated by the levels of tubulointerstitial fibrosis. Immunohistochemical analysis of intrarenal (P)RR and cell surface markers (cluster of differentiation [CD]3, CD19, and CD68) was performed on samples taken from the removed kidney. Moreover, double staining of (P)RR and cell surface markers was also performed.ResultsThere were significant positive relationships between plasma s(P)RR and tubulointerstitial fibrosis in all the patients and those not receiving RAS blocker therapy. Significant positive relationships were found between plasma s(P)RR levels and the extent of tubulointerstitial fibrosis after adjustment for age, sex, body weight, blood pressure, and plasma angiotensin II, in all the patients and those not receiving RAS blockers. Moreover, (P)RR expression was elevated in infiltrated mononuclear cells but not connecting tubules or collecting ducts and vessels. Infiltrated cells positive for (P)RR consisted of CD3 and CD68 but not CD19.ConclusionsThese data suggest that plasma s(P)RR levels may reflect (P)RR expression levels in infiltrated mononuclear cells, which can be a surrogate marker of renal damage.
| S-EPMC4881895 | biostudies-literature
Project description:The renin-angiotensin system (RAS), a key regulator of the blood pressure and fluid/electrolyte homeostasis, also plays a critical role in kidney development. All the components of the RAS are expressed in the developing metanephros. Moreover, mutations in the genes encoding components of the RAS in mice or humans are associated with a broad spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). These forms of CAKUT include renal papillary hypoplasia, hydronephrosis, duplicated collecting system, renal tubular dysgenesis, renal vascular abnormalities, and aberrant glomerulogenesis. Emerging evidence indicates that (pro)renin receptor (PRR), a novel component of the RAS, is essential for proper kidney development and that aberrant PRR signaling is causally linked to cardiovascular and renal disease. This paper describes the role of the RAS in kidney development and highlights emerging insights into the cellular and molecular mechanisms by which the PRR may regulate this critical morphogenetic process.
| S-EPMC3132641 | biostudies-literature
Project description:Proteinuria is a characteristic of chronic kidney disease and also a causative factor that promotes the disease progression, in part, via activation of the intrarenal renin-angiotensin system (RAS). (Pro)renin receptor (PRR), a newly discovered component of the RAS, binds renin and (pro)renin to promote angiotensin I generation. The present study was performed to test the role of soluble PRR (sPRR) in albumin overload-induced responses in cultured human renal proximal tubular cell line human kidney 2 (HK-2) cells. Bovine serum albmuin (BSA) treatment for 24 h at 20 mg/ml induced renin activity and inflammation, both of which were attenuated by a PRR decoy inhibitor PRO20. BSA treatment induced a more than fivefold increase in medium sPRR due to enhanced cleavage of PRR. Surprisingly, this cleavage event was unaffected by inhibition of furin or a disintegrin and metalloproteinase 19. Screening for a novel cleavage enzyme led to the identification of site-1 protease (S1P). Inhibition of S1P with PF-429242 or siRNA remarkably suppressed BSA-induced sPRR production, renin activity, and inflammatory response. Administration of a recombinant sPRR, termed sPRR-His, reversed the effects of S1P inhibition. In HK-2 cells overexpressing PRR, mutagenesis of the S1P, but not furin cleavage site, reduced sPRR levels. Together, these results suggest that PRR mediates albumin-induced cellular responses through S1P-derived sPRR.
| S-EPMC5814590 | biostudies-literature