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Circular RNAs (circRNAs) are a class of non-coding RNAs that regulate gene expression by acting as competitive endogenous RNAs (ceRNAs) and modulating gene transcription. Several studies support the implication of circRNAs in a variety of human diseases, but research on the role of circRNAs in systemic lupus erythematosus (SLE) is lacking. In a study recently published in Clinical Science (2018), Zhang et al. identified hsa circ 0012919 as a potential biomarker of disease activity in SLE patients. The authors observed different circRNA expression between SLE patients and healthy controls, an association with clinical variables and with the abnormal DNA methylation present in SLE CD4+ T cells. Finally, Zhang et al. demonstrated that hsa circ 0012919 acts as a miRNA sponge for miR-125a-3p, regulating the gene expression of targets RANTES and KLF13 that are involved in the physiology and pathophysiology of acute and chronic inflammatory processes. These findings support the role of circRNAs in the pathophysiology of SLE. [ABSTRACT FROM AUTHOR]

Background and Aims Familial hypercholesterolemia (FH) is associated with higher levels of inflammatory mediators such as chemokines, which contribute to an increased risk of premature atherosclerosis in these patients. We studied the response of chemokines related to early atherosclerotic processes during an oral unsaturated fat load test (OFLT) in patients with heterozygous FH and compared this response to normolipidemic and normoglycemic subjects. Methods Blood samples were taken from 12 FH patients and 20 healthy controls with a similar age, gender distribution, and body mass index. Plasma chemokine levels were determined in both groups in a fasting state and at 2, 4, 6, and 8 h after an OFLT using human cytokine multiplex kits (Linco) and a Luminex LABScan™100 system. Results In the fasting state MIP-1β, MIP-1α, IP-10, IFN-γ, MCP-1, and IL-8 were significantly increased in the FH group compared to the healthy controls ( p <0.05). In addition, a significant decrease in postprandial chemokine plasma values were found in the FH group compared to fasting values after the OFLT. In normolipidemic nondiabetic controls no significant changes were found in the postprandial state. Conclusions There was a postprandial decrease in chemokines related to early atherosclerotic processes after an OFLT in FH patients. These results confirm the influence of dietary patterns in this group of patients. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus is an autoimmune disease that predominantly affects women and typically manifests in multiple organs. The damage caused by this disorder is characterized by a chronic inflammatory state. Extracellular vesicles (EVs), including microvesicles (also known as microparticles), apoptotic bodies, and exosomes, are recognized vehicles of intercellular communication, carrying autoantigens, cytokines, and surface receptors. Therefore, the evidence of EVs and their cargo as biomarkers of autoimmune disease is rapidly expanding. This review will focus on biogenesis of extracellular vesicles, their pathophysiological roles, and their potential as biomarkers and therapeutics in inflammatory disease, especially in systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Objectives Familial hypercholesterolemia (FH) is characterized by increased oxidative stress (OS) levels. In the postprandial state, lipids and lipoproteins modulate OS status through their impact on pro-oxidant and antioxidant mechanisms. The objective of this study was to evaluate in patients with FH the response to an unsaturated oral fat load test (OFLT) by analyzing the mRNA levels of genes involved in the glutathione and thioredoxin antioxidant systems. Design and Methods We analyzed 14 FH patients and 20 normolipidemic and normoglycemic controls. In both groups, mRNA values of antioxidant enzyme genes (glutathione and thioredoxin systems) were determined at baseline and at 2, 4, 6, and 8 h after OFLT by real time PCR. Results In the fasting state the mRNA levels of antioxidant enzymes GPX4 and the GSR, GSS, and GCLC enzymes (involved in glutathione regeneration and synthesis) and thioredoxin (TXN), were significantly increased in the FH group compared to the healthy controls. Some genes (GPX1 and GPX4) were increased at 4 h in both groups, but values for the rest of the antioxidant enzyme mRNAs were decreased in FH patients after 4 h from unsaturated OFLT and were increased in controls. Conclusions We concluded that an OFLT with predominantly unsaturated fat has a different effect on postprandial antioxidant enzyme mRNA levels in controls than in FH patients. Increased antioxidant enzyme mRNA is not the main way to reduce postprandial oxidative stress in FH. This difference could determine the influence of dietary patterns in these patients. [ABSTRACT FROM AUTHOR]

Artificial Intelligence is creating a paradigm shift in health care, with phenotyping patients through clustering techniques being one of the areas of interest. Objective: To develop a predictive model to classify heart failure (HF) patients according to their left ventricular ejection fraction (LVEF), by using available data from Electronic Health Records (EHR). Subjects and methods: 2854 subjects over 25 years old with a diagnosis of HF and LVEF, measured by echocardiography, were selected to develop an algorithm to predict patients with reduced EF using supervised analysis. The performance of the developed algorithm was tested in heart failure patients from Primary Care. To select the most influentual variables, the LASSO algorithm setting was used, and to tackle the issue of one class exceeding the other one by a large amount, we used the Synthetic Minority Oversampling Technique (SMOTE). Finally, Random Forest (RF) and XGBoost models were constructed. Results: The full XGBoost model obtained the maximum accuracy, a high negative predictive value, and the highest positive predictive value. Gender, age, unstable angina, atrial fibrillation and acute myocardial infarct are the variables that most influence EF value. Applied in the EHR dataset, with a total of 25,594 patients with an ICD-code of HF and no regular follow-up in cardiology clinics, 6170 (21.1%) were identified as pertaining to the reduced EF group. Conclusion: The obtained algorithm was able to identify a number of HF patients with reduced ejection fraction, who could benefit from a protocol with a strong possibility of success. Furthermore, the methodology can be used for studies using data extracted from the Electronic Health Records. [ABSTRACT FROM AUTHOR]

• A renewed interest exists in miRNAs as biomarkers in cardiovascular disease. • miR-126–3p is associated with albuminuria, a marker of endothelial dysfunction, in hypertension. • High miR-126–3p levels are associated with cardiovascular events in general population. Endothelial dysfunction is a forerunner of atherosclerosis, leading to cardiovascular disease, and albuminuria is a marker of endothelial dysfunction. Circulating levels of microRNAs are emerging as potential biomarkers for cardiovascular disease. Here we estimate the predictive value of a plasma microRNAs signature associated with albuminuria in the incidence of cardiovascular events. Plasma microRNAs quantified in hypertensive patients by next generation sequencing were validated in a cohort of patients and controls by real-time quantitative PCR. The microRNAs found to be associated with albuminuria were analysed for their prognostic value in predicting cardiovascular events incidence on a retrospective, population-based study (Hortega Study), using Cox proportional hazard models. A plasma microRNA profile was identified in the discovery cohort (n = 48) associated with albuminuria and three microRNAs (miR-126–3p, miR-1260b and miR-374a-5p) were confirmed in the validation cohort (n = 98). The microRNA signature discriminates urinary albumin excretion at baseline (n = 1025), and predicts the incidence of cardiovascular events and coronary heart disease and stroke in a general population retrospective study within a 14-year follow-up (n = 926). High miR-126–3p levels were associated with a shorter time free of both cardiovascular events (HR=1.48, (1.36–1.62), p < 0.0001), as well as coronary artery disease and stroke combined (HR=2.49, (2.19–2.83), p < 0.0001). An increased plasma microRNAs profile was identified in hypertensive patients with albuminuria. Increased miR-126–3p suggest it may serve as a prognostic marker for cardiovascular events in a long-term general population. Further studies will assess the potential role of miR-126–3p as a guide for the status of endothelial dysfunction. Circulating miR-126–3p as a prognostic marker of MACE and combined CAD and stroke in a long-term general population cohort. A signature of 4 miRNAs is associated with albuminuria in the discovery and validation cohorts of hypertensive patients and controls. in a general population cohort (Hortega testing cohort) followed during 14 years, increased levels of plasma circulating miR-126–3p are associated with the incidence of MACE (major adverse cardiovascular events) and combined CAD (coronary artery disease) and stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

Simple Summary: In diabetic nephropathy, the injury of renal cells such as podocytes worsens the glomerular filtration process due to the cells' loss and detachment from the basal membrane. Intra- and intercellular communications in cells are partially mediated by the Rab3A/Rab27A system. We have observed that silencing the Rab3A/Rab27A system in podocytes experiencing glucose overload has a differential impact on differentiation, cytoskeleton organisation, apoptosis, CD63 distribution, and miRNA levels. Generally, when cells are subjected to glucose stress and the Rab system is silenced, we observed a reduction in the detrimental cell processes. These results suggest that the Rab3A/Rab27A system is a key participant in podocyte injury and vesicular traffic regulation in diabetic nephropathy. Diabetic nephropathy is a major complication in diabetic patients. Podocytes undergo loss and detachment from the basal membrane. Intra- and intercellular communication through exosomes are key processes for maintaining function, and the Rab3A/Rab27A system is an important counterpart. Previously, we observed significant changes in the Rab3A/Rab27A system in podocytes under glucose overload, demonstrating its important role in podocyte injury. We investigated the implication of silencing the Rab3A/Rab27A system in high glucose-treated podocytes and analysed the effect on differentiation, apoptosis, cytoskeletal organisation, vesicle distribution, and microRNA expression in cells and exosomes. For this, we subjected podocytes to high glucose and transfection through siRNAs, and we isolated extracellular vesicles and performed western blotting, transmission electron microscopy, RT-qPCR, immunofluorescence and flow cytometry assays. We found that silencing RAB3A and RAB27A generally leads to a decrease in podocyte differentiation and cytoskeleton organization and an increase in apoptosis. Moreover, CD63-positive vesicles experienced a pattern distribution change. Under high glucose, Rab3A/Rab27A silencing ameliorates some of these detrimental processes, suggesting a differential influence depending on the presence or absence of cellular stress. We also observed substantial expression changes in miRNAs that were relevant in diabetic nephropathy upon silencing and glucose treatment. Our findings highlight the Rab3A/Rab27A system as a key participant in podocyte injury and vesicular traffic regulation in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Despite considerable progress in our understanding of systemic lupus erythematosus (SLE) pathophysiology, patient diagnosis is often deficient and late, and this has an impact on disease progression. The aim of this study was to analyze non-coding RNA (ncRNA) packaged into exosomes by next-generation sequencing to assess the molecular profile associated with renal damage, one of the most serious complications of SLE, to identify new potential targets to improve disease diagnosis and management using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The plasma exosomes had a specific ncRNA profile associated with lupus nephritis (LN). The three ncRNA types with the highest number of differentially expressed transcripts were microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and piwi-interacting RNAs (piRNAs). We identified an exosomal 29-ncRNA molecular signature, of which 15 were associated only with LN presence; piRNAs were the most representative, followed by lncRNAs and miRNAs. The transcriptional regulatory network showed a significant role for four lncRNAs (LINC01015, LINC01986, AC087257.1 and AC022596.1) and two miRNAs (miR-16-5p and miR-101-3p) in network organization, targeting critical pathways implicated in inflammation, fibrosis, epithelial–mesenchymal transition and actin cytoskeleton. From these, a handful of potential targets, such as transforming growth factor-β (TGF-β) superfamily binding proteins (activin-A, TGFB receptors, etc.), WNT/β-catenin and fibroblast growth factors (FGFs) have been identified for use as therapeutic targets of renal damage in SLE. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that affects multiple organs. Currently, therapeutic molecules present adverse side effects and are only effective in some SLE patient subgroups. Extracellular vesicles (EV), including exosomes, microvesicles and apoptotic bodies, are released by most cell types, carry nucleic acids, proteins and lipids and play a crucial role in cell-to-cell communication. EVs can stimulate or suppress the immune responses depending on the context. In SLE, EVs can work as autoadjuvants, enhance immune complex formation and maintaining inflammation state. Over the last years, EVs derived from mesenchymal stem cells and antigen presenting cells have emerged as cell-free therapeutic agents to treat autoimmune and inflammatory diseases. In this review, we summarize the current therapeutic applications of extracellular vesicles to regulate immune responses and to ameliorate disease activity in SLE and other autoimmune disorders. [ABSTRACT FROM AUTHOR]

Context:Heliopsis longipes(A. Gray) Blake (Asteraceae), a plant native to Mexico, is used in traditional medicine as analgesic and microbicide. The main component in theH. longipesethanolic extract (HLEE) is affinin, as determined by HPLC/UV–visible and NMR measurement. To date, there is no documented evidence on the spermicidal activity of this extract. Objective: The objective of this study was to assessin vitrothe effectiveness of HLEE as spermicide. Materials and methods: The spermicidal activity of HLEE was evaluated by the Sander–Cramer assay. Spermatozoa were incubated for 20 s with HLEE in concentrations ranging from 75 to 2000 µg/mL to determine the minimum effective concentration (MEC) value. The 50% effective concentration (EC50) of HLEE was estimated by assaying serial dilutions from the MEC. Additionally, sperms were incubated with 125, 250, or 500 µg/mL of HLEE to evaluate the viability and the integrity of sperm membrane. Lipid peroxidation was assessed by the thiobarbituric acid reactive substances assay. Results: HLEE caused an inhibition of 100% in spermatozoa motility at a MEC value of 2000 µg/mL; the EC50value was 125 µg/mL. Additionally, exposure to HLEE at 125, 250, or 500 µg/mL for 30 min decreased sperm viability to 27%, 8%, and 2% of the control value, respectively, and significantly increased the percentage of sperms with structurally disorganized membrane. HLEE also increased significantly the level of lipid peroxidation in sperms with respect to controls. Discussion and conclusion: The results demonstrate the spermicidal activity of HLEEin vitroand suggest that this action is caused by oxidative damage and alterations in the spermatozoal membrane. [ABSTRACT FROM PUBLISHER]

Non-coding RNA (ncRNA)-mediated targeting of various genes regulates the molecular mechanisms of the pathogenesis of hypertension (HTN). However, very few circulating long ncRNAs (lncRNAs) have been reported to be altered in essential HTN. The aim of our study was to identify a lncRNA profile in plasma and plasma exosomes associated with urinary albumin excretion in HTN by next-generation sequencing and to assess biological functions enriched in response to albuminuria using GO and KEGG analysis. Plasma exosomes showed higher diversity and fold change of lncRNAs than plasma, and low transcript overlapping was found between the two biofluids. Enrichment analysis identified different biological pathways regulated in plasma or exosome fraction, which were implicated in fatty acid metabolism, extracellular matrix, and mechanisms of sorting ncRNAs into exosomes, while plasma pathways were implicated in genome reorganization, interference with RNA polymerase, and as scaffolds for assembling transcriptional regulators. Our study found a biofluid specific lncRNA profile associated with albuminuria, with higher diversity in exosomal fraction, which identifies several potential targets that may be utilized to study mechanisms of albuminuria and cardiovascular damage. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (ADs) are characterized by the activation of the immune system against self-antigens. More common in women than in men and with an early onset, their incidence is increasing worldwide, and this, combined with their chronic nature, is contributing to an enlarged medical and economic burden. Conventional immunosuppressive agents are designed to alleviate symptoms but do not constitute an effective therapy, highlighting a need to develop new alternatives. In this regard, mesenchymal stem cells (MSCs) have demonstrated powerful immunosuppressive and regenerative effects. MSC-derived extracellular vesicles (MSC-EVs) have shown some advantages, such as less immunogenicity, and are proposed as novel therapies for ADs. In this review, we summarize current perspectives on therapeutic options for ADs based on MSCs and MSC-EVs, focusing particularly on their mechanism of action exerted through their non-coding RNA (ncRNA) cargo. A complete state-of-the-art review was performed, centralized on some of the most severe ADs (rheumatoid arthritis, autoimmune type 1 diabetes mellitus, and systemic lupus erythematosus), giving evidence that a promising field is evolving to overcome the current knowledge and provide new therapeutic possibilities centered on MSC-EVs and their role as ncRNA delivery vehicles for AD gene therapy. [ABSTRACT FROM AUTHOR]

Kidney injury in hypertension and diabetes entails, among in other structures, damage in a key cell of the glomerular filtration barrier, the podocyte. Podocytes are polarized and highly differentiated cells in which vesicular transport, partly driven by Rab GTPases, is a relevant process. The aim of the present study was to analyze Rab GTPases of the Rab-Rabphilin system in human immortalized podocytes and the impact of high glucose and angiotensin II. Furthermore, alterations of the system in urine cell pellets from patients with hypertension and diabetes were studied. Apoptosis was analyzed in podocytes, and mRNA level quantification, Western blot analysis, and immunofluorescence were developed to quantify podocyte-specific molecules and Rab-Rabphilin components (Rab3A, Rab27A, and Rabphilin3A). Quantitative RTPCR was performed on urinary cell pellet from patients. The results showed that differentiated cells had reduced protein levels of the Rab-rabphillin system compared with undifferentiated cells. After glucose overload and angiotensin II treatment, apoptosis was increased and podocyte-specific proteins were reduced. Rab3A and Rab27A protein levels were increased under glucose overload, and Rabphilin3A decreased. Furthermore, this system exhibited higher levels under stress conditions in a manner of angiotensin II dose and time treatment. Immunofluorescence imaging indicated different expression patterns of podocyte markers and Rab27A under treatments. Finally, Rab3A and Rab27A were increased in patient urine pellets and showed a direct relationship with albuminuria. Collectively, these results suggest that the Rab-Rabphilin system could be involved in the alterations observed in injured podocytes and that a mechanism may be activated to reduce damage through the vesicular transport enhancement directed by this system. [ABSTRACT FROM AUTHOR]

Background: Sequencing of miRNAs isolated from exosomes has great potential to identify novel disease biomarkers, but exosomes have low amount of RNA, hindering adequate analysis and quantification. Here, we have assessed several steps in developing an optimized small RNA (sRNA) library preparation protocol for next-generation sequencing (NGS) miRNA analysis from urinary exosomes.Methods: A total of 24 urinary exosome samples from donors were included in this study. RNA was extracted by column-based methods. The quality of extracted RNA was assessed by spectrophotometric quantification and Bioanalyzer software analysis. All libraries were prepared using the CleanTag small RNA library preparation protocol and the effect of our additional modifications on adapter-dimer presence, sequencing data and tagged small RNA library population was also analyzed.Results: Our results show that good quality sequencing libraries can be prepared following our optimized small RNA library preparation protocol from urinary exosomes. When the size selection by gel purification step was included within the workflow, adapter-dimer was totally removed from cDNA libraries. Furthermore, the inclusion of this modification step within small RNA library protocol augmented the small RNA mapped reads, with an especially significant 37% increase in miRNA reads, and the gel purification step made no difference to the tagged miRNA population.Conclusions: This study provides researchers with an optimized small RNA library preparation workflow for next generation sequencing based exosome-associated miRNA analysis that yields a high amount of miRNA mapped reads without skewing the tagged miRNA population significantly. [ABSTRACT FROM AUTHOR]

Identifying new markers of disease flares in lupus nephritis (LN) that facilitate patient stratification and prognosis is important. Therefore, the aim of the present study was to analyze whether urinary SIRT1 expression was altered in LN and whether SIRT1 values in urine could be valuable biomarker of disease activity. In a cohort study, urinary pellets from 40 patients diagnosed with systemic lupus erythematosus (SLE) were analyzed. Clinical measures of lupus activity were assessed. The expression of SIRT1 was quantified by quantitative PCR (qRT-PCR) and immunoblot, then compared between patients with active lupus nephritis, in remission and healthy controls. Association with lupus activity and renal histological features was also analyzed. A significant increase in SIRT1 mRNA levels in patients with active LN was observed compared with those in remission (P=0.02) or healthy controls (P=0.009). In addition, SIRT-1 protein levels were also augmented in LN group than remission (P=0.029) and controls (P=0.001). A strong association was found between SIRT1 expression with anti-dsDNA in SLE and in patients with LN. In addition, histological features in LN biopsies were related with SIRT1, increasing its expression in proliferative forms. Finally, SIRT1 expression values showed a strong discriminatory power of renal injury in SLE. Our study demonstrated an altered urinary expression of SIRT1 and a strong association with disease activity in LN patients, being a valuable marker of renal injury. These results showed the role of the SIRT1 pathway in the SLE pathogenesis. [ABSTRACT FROM AUTHOR]

Background. Currently, renal biopsy remains the gold standard for the diagnosis and prognosis of lupus nephritis (LN). However, it is an invasive method, and new non-invasive laboratory tests are needed to identify renal involvement without renal biopsy. Podocyte damage plays an important role in the pathogenesis and progression of systemic lupus erythematosus (SLE). We characterize whether the phenotype of urinary podocytes (viability, apoptosis, mRNA and protein levels of the podocyteassociated molecules) is a novel marker of clinical and histological features in SLE patients with or without LN. Methods. We quantified in urinary sediments of 32 SLE patients and 20 controls, mRNA and protein levels of podocalyxin, synapotopodin, podocin, nephrin andWT-1 by quantitative real-time polymerase chain reaction and western blot analysis and correlated thesewith clinical and histological parameters. The viability of detached urine podocytes was analysed by flow cytometry with podocalyxin and annexin V/7-AAD double staining and immunofluorescence of urine podocyte cultures. Results. The degree of a poptotic podocytes from urine samples was significantly decreased in patients with LN, especially in the active state (33% compared with 75% in controls, P < 0.001), and the majority of the detached podocytes in the urine of patients with active LN were viable (70% grew in culture). Furthermore, urinary mRNA of podocyte-associated molecules was significantly lower in patients with active LN (P < 0.05) compared with healthy controls, and protein levels of podocyte markers were significantly increased in SLE patients, especially with LN compared with SLE without LN (P < 0.05) and the healthy control group (P < 0.01). Finally, urinary protein levels of podocyte-related markers were associated with proteinuria and histological features (P < 0.05 and P < 0.01), and receiver operating characteristics curves of protein levels discriminate between LN and healthy controls with an area under the curve (AUC) between 0.91 and 0.77 (P < 0.001). Conclusions. Urinary dedifferentiated podocytes were shown in active LN, and their protein levels correlated with proteinuria and histological features in LN. These preliminary results suggest that it could be a potentially useful non-invasive marker for evaluating the progression of glomerular disease in SLE. [ABSTRACT FROM AUTHOR]

There is increased interest in using microRNAs (miRNAs) as biomarkers in different diseases. Present in body fluids, it is controversial whether or not they are mainly enclosed in exosomes, thus we studied if urinary miRNAs are concentrated inside exosomes and if the presence of systemic lupus erythematosus with or without lupus nephritis modifies their distribution pattern. We quantified specific miRNAs in urine of patients with systemic lupus erythematosus (n = 38) and healthy controls (n = 12) by quantitative reverse-transcription PCR in cell-free urine, exosome-depleted supernatant and exosome pellet obtained by ultracentrifugation. In control group, miR-335* and miR-302d were consistently higher in exosomes than in exosome-depleted supernatant, and miR-200c and miR-146a were higher in cell-free fraction. In lupus patients, all urinary miRNAs tested were mainly in exosomes with lower levels outside them (p<0.05 and p<0.01, respectively). This pattern is especially relevant in patients with active lupus nephritis compared to the control group or to the SLE patients in absence of lupus nephritis, with miR-146a being the most augmented (100-fold change, p<0.001). Among the exosomal miRNAs tested, only the miR-146a discriminates the presence of active lupus nephritis. In conclusion, urinary miRNAs are contained primarily in exosomes in systemic lupus erythematosus, and the main increment was found in the presence of active lupus nephritis. These findings underscore the attractiveness of exosomal miRNAs in urine, a non-invasive method, as potential renal disease markers. [ABSTRACT FROM AUTHOR]

Non-coding RNA (ncRNA), released into circulation or packaged into exosomes, plays important roles in many biological processes in the kidney. The purpose of the present study is to identify a common ncRNA signature associated with early renal damage and its related molecular pathways. Three individual libraries (plasma and urinary exosomes, and total plasma) were prepared from each hypertensive patient (with or without albuminuria) for ncRNA sequencing analysis. Next, an RNA-based transcriptional regulatory network was constructed. The three RNA biotypes with the greatest number of differentially expressed transcripts were long-ncRNA (lncRNA), microRNA (miRNA) and piwi-interacting RNA (piRNAs). We identified a common 24 ncRNA molecular signature related to hypertension-associated urinary albumin excretion, of which lncRNAs were the most representative. In addition, the transcriptional regulatory network showed five lncRNAs (LINC02614, BAALC-AS1, FAM230B, LOC100505824 and LINC01484) and the miR-301a-3p to play a significant role in network organization and targeting critical pathways regulating filtration barrier integrity and tubule reabsorption. Our study found an ncRNA profile associated with albuminuria, independent of biofluid origin (urine or plasma, circulating or in exosomes) that identifies a handful of potential targets, which may be utilized to study mechanisms of albuminuria and cardiovascular damage. [ABSTRACT FROM AUTHOR]

Small Rab GTPases, the largest group of small monomeric GTPases, regulate vesicle trafficking in cells, which are integral to many cellular processes. Their role in neurological diseases, such as cancer and inflammation have been extensively studied, but their implication in kidney disease has not been researched in depth. Rab3a and its effector Rabphillin-3A (Rph3A) expression have been demonstrated to be present in the podocytes of normal kidneys of mice rats and humans, around vesicles contained in the foot processes, and they are overexpressed in diseases with proteinuria. In addition, the Rab3A knockout mice model induced profound cytoskeletal changes in podocytes of high glucose fed animals. Likewise, RphA interference in the Drosophila model produced structural and functional damage in nephrocytes with reduction in filtration capacities and nephrocyte number. Changes in the structure of cardiac fiber in the same RphA-interference model, open the question if Rab3A dysfunction would produce simultaneous damage in the heart and kidney cells, an attractive field that will require attention in the future. [ABSTRACT FROM AUTHOR]

Exosomes, nanometer-sized lipid-bilayer-enclosed extracellular vesicles (EVs), have attracted increasing attention due to their inherent ability to shuttle proteins, lipids and genes between cells and their natural affinity to target cells. Their intrinsic features such as stability, biocompatibility, low immunogenicity and ability to overcome biological barriers, have prompted interest in using exosomes as drug delivery vehicles, especially for gene therapy. Evidence indicates that exosomes play roles in both immune stimulation and tolerance, regulating immune signaling and inflammation. To date, exosome-based nanocarriers delivering small molecule drugs have been developed to treat many prevalent autoimmune diseases. This review highlights the key features of exosomes as drug delivery vehicles, such as therapeutic cargo, use of targeting peptide, loading method and administration route with a broad focus. In addition, we outline the current state of evidence in the field of exosome-based drug delivery systems in systemic lupus erythematosus (SLE), evaluating exosomes derived from various cell types and engineered exosomes. [ABSTRACT FROM AUTHOR]

Sirtuins have become important players in renal damage in hypertension and diabetes, but their value as biomarkers is poorly assessed. The aims of the study were to evaluate the levels of sirtuin1 (SIRT1), and two miRNAs that regulate SIRT1 expression in hypertensive patients with incipient renal damage with and without diabetes. We quantified urinary SIRT1 and claudin 1 (CLDN1) mRNA and miR34-a and miR-200a levels by quantitative real-time polymerase chain reaction (RT-qPCR) from patients and in cultured podocytes treated with high glucose and angiotensin II. Western blot and fluorescence analyses were also performed. We found decreased SIRT1 levels in patients with increased urinary albumin excretion (UAE), the lowest with diabetes presence, and a strong association with UAE, discriminating incipient renal damage. In vitro experiments also showed SIRT1 overall decreases in podocyte cultures under treatment conditions. In urine samples, miR-34a was reduced and miR-200a increased, both related to UAE levels. However, both miRNAs were generally increased in podocyte cultures under high glucose and angiotensin-II treatment. These results show a significant urinary SIRT1 decrease in albuminuric hypertensive patients, strongly associated with albuminuria, suggesting that SIRT1 could be a potential and non-invasive method to assess incipient renal damage in hypertensive patients. [ABSTRACT FROM AUTHOR]

Background: There is increasing interest in using extracellular vesicle-derived microRNAs (miRNAs) as biomarkers in renal dysfunction and injury. Preliminary evidence indicates that miRNAs regulate the progression of glomerular disease. Indeed, exosomes from the renal system have provided novel evidence in the clinical setting of albuminuria. Thus, the aim of this study was to quantify the urinary miRNAs present in exosome and microvesicles (MVs), and to assess their association with the presence of increased urinary albumin excretion in essential hypertension.Methods: Exosomes were collected from urine specimens from a cohort of hypertensive patients with (n = 24) or without albuminuria (n = 28), and from 20 healthy volunteers as a control group. Urinary exosomes were phenotyped by Western blot, tunable resistive pulse sensing, and electronic microscopy. Expression of miR-146a and miR-335* was analysed by qRT-PCR and any associations between albuminuria and exosomal miRNAs were analysed.Results: Urinary miRNAs are highly enriched in exosome subpopulations compared to MVs, both in patients with or without increased albuminuria (p < 0.001), but not in the control group. High albuminuria was associated with 2.5-fold less miR-146a in exosomes (p = 0.017), whereas miR-146a levels in MV did not change. In addition, exosome miR-146a levels were inversely associated with albuminuria (r = 0.65, p < 0.0001), and discriminated the presence of urinary albumin excretion presence [area under the curve = 0.80, 95% confidence interval: 0.66-0.95; p = 0.0013].Conclusions: Our results indicate that miRNAs were enriched in the urinary exosome subpopulation in hypertensive patients and that low miR-146a expression in exosomes was associated with the presence of albuminuria. Thus, urinary exosome miR-146a may be a potentially useful tool for studying early renal injury in hypertension. [ABSTRACT FROM AUTHOR]