In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with increased morbidity and mortality and thus poses a major challenge for healthcare systems. While the contribution of tissue-derived miRNAs and mRNAs to CKD progression has been extensively studied, little is known about the role of urinary exosomes and their association with CKD. Exosomes are small, membrane-derived endocytic vesicles that contribute to cell-to-cell communication and are present in various body fluids, such as blood or urine. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential for sensitive nucleic acid biomarkers in various human diseases. Therefore, in this study we aimed to identify urinary exosomal ncRNAs as novel biomarkers for diagnosis of CKD. Since up to now most approaches have focused on the class of miRNAs, we extended our analysis to several other noncoding RNA classes, such as tRNAs, tRNA fragments (tRFs), mitochondrial tRNAs, or lincRNAs. For their computational identification from RNA-seq data, we developed a novel computational pipeline, designated as ncRNASeqScan. By these analyses, in CKD patients we identified 30 differentially expressed ncRNAs, derived from urinary exosomes, as suitable biomarkers for early diagnosis. Thereby, miRNA-181a appeared as the most robust and stable potential biomarker, being significantly decreased by about 200-fold in exosomes of CKD patients compared to healthy controls. Using a cell culture system for CKD indicated that urinary exosomes might indeed originate from renal proximal tubular epithelial cells.

/pdf/identification-of-urinary-exosomal-noncoding-rnas-as-novel-tcdr7zfnf6.pdf

Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease

Idiopathic nephrotic syndrome (INS) describes a group of pathologies of the renal glomerulus that result in the classic triad of heavy proteinuria, oedema and hypoalbuminaemia. The disease has historically been defined by evidence of distinctive histological changes in the absence of clinical evidence of a distinct pathological driver. However, the current classification is not based on any systematic mechanistic understanding of biological processes, and therefore current treatment regimens are broad, iterative and nonspecific. Over the past 20 years delineation of the underlying biology of the target cell in INS — the glomerular podocyte — has transformed our understanding of the mechanisms that contribute to breakdown of the glomerular filtration barrier and the development of INS. It is increasingly clear that nephrotic syndrome caused by monogenic mutations is distinct from immune-driven disease, which in some cases is mediated by circulating factors that target the podocyte. The combination of systems biology and bioinformatics approaches, together with powerful laboratory models and ever-growing patient registries has potential to identify disease ‘signatures’ that reflect the underlying molecular mechanism of INS on an individual basis. Understanding of such processes could lead to the development of targeted therapies. Greater understanding of podocyte biology has improved our understanding of the mechanisms that contribute to the development of nephrotic syndrome. Here, Saleem outlines how our understanding of disease mechanisms that contribute to nephrotic syndrome could transform the classification and treatment of this disease.

Molecular stratification of idiopathic nephrotic syndrome

MicroRNAs (miRNA) are varied in length, under 25 nucleotides, single-stranded noncoding RNA that regulate post-transcriptional gene expression via translational repression or mRNA degradation. Elevated levels of miRNAs can be detected in systemic circulation after tissue injury, suggesting that miRNAs are released following cellular damage. Because of their remarkable stability, ease of detection in biofluids, and tissue specific expression patterns, miRNAs have the potential to be specific biomarkers of organ injury. The identification of miRNA biomarkers requires a systematic approach: 1) determine the miRNA tissue expression profiles within a mammalian species via next generation sequencing; 2) identify enriched and/or specific miRNA expression within organs of toxicologic interest, and 3) in vivo validation with tissue-specific toxicants. While miRNA tissue expression has been reported in rodents and humans, little data exists on miRNA tissue expression in the dog, a relevant toxicology species. The generation and evaluation of the first dog miRNA tissue atlas is described here. Analysis of 16 tissues from five male beagle dogs identified 106 tissue enriched miRNAs, 60 of which were highly enriched in a single organ, and thus may serve as biomarkers of organ injury. A proof of concept study in dogs dosed with hepatotoxicants evaluated a qPCR panel of 15 tissue enriched miRNAs specific to liver, heart, skeletal muscle, pancreas, testes, and brain. Dogs with elevated serum levels of miR-122 and miR-885 had a correlative increase of alanine aminotransferase, and microscopic analysis confirmed liver damage. Other non-liver enriched miRNAs included in the screening panel were unaffected. Eli Lilly authors created a complimentary Sprague Dawely rat miRNA tissue atlas and demonstrated increased pancreas enriched miRNA levels in circulation, following caerulein administration in rat and dog. The dog miRNA tissue atlas provides a resource for biomarker discovery and can be further mined with refinement of dog genome annotation. The 60 highly enriched tissue miRNAs identified within the dog miRNA tissue atlas could serve as diagnostic biomarkers and will require further validation by in vivo correlation to histopathology. Once validated, these tissue enriched miRNAs could be combined into a powerful qPCR screening panel to identify organ toxicity during early drug development.

/pdf/the-beagle-dog-microrna-tissue-atlas-identifying-1vmcxfka8y.pdf

The beagle dog MicroRNA tissue atlas: identifying translatable biomarkers of organ toxicity

Urine has the potential to become a better source of biomarkers. Urinary proteins are affected by many factors; therefore, differentiating between the variables associated with any particular pathophysiological condition in clinical samples is challenging. To circumvent these problems, simpler systems, such as animal models, should be used to establish a direct relationship between disease progression and urine changes. In this study, a unilateral ureteral obstruction (UUO) model was used to observe tubular injury and the eventual development of renal fibrosis, as well as to identify differential urinary proteins in this process. Urine samples were collected from the residuary ureter linked to the kidney at 1 and 3 weeks after UUO. Five hundred proteins were identified and quantified by LC-MS/MS, out of which 7 and 19 significantly changed in the UUO 1- and 3-week groups, respectively, compared with the sham-operation group. Validation by western blot showed increased levels of Alpha-actinin-1 and Moesin in the UUO 1-week group, indicating that they may serve as candidate biomarkers of renal tubular injury, and significantly increased levels of Vimentin, Annexin A1 and Clusterin in the UUO 3-week group, indicating that they may serve as candidate biomarkers of interstitial fibrosis.

/pdf/urinary-candidate-biomarker-discovery-in-a-rat-unilateral-4ph1v2qecr.pdf

Urinary candidate biomarker discovery in a rat unilateral ureteral obstruction model

Urine has the potential to become a better source of biomarkers. Urinary proteins are affected by many factors; therefore, differentiating between the variables associated with any particular patho...

Urinary Candidate Biomarker Discovery in a Rat Unilateral Ureteral Obstruction Model

Introduction. Recent studies have shown that serum microRNAs have specific expression patterns in some diseases, indicating the potential of using microRNAs to aid diagnosis. This study estimated the levels of microRNAs in patients with nephrotic syndrome compared with healthy controls. Materials and Methods. In this study, real-time quantitative polymerase chain reaction was used to explore whether there were different expression levels of miR-181a, miR-483-5p, and miR-557 in the serum of patients with nephrotic syndrome subtypes and healthy controls. We measured the three microRNAs in 40 patients with nephrotic syndrome and 16 healthy controls. Results. The circulating levels of miR-483-5p and miR-557 were not significantly upregulated or downregulated, whereas miR-181a was significantly upregulated in patients with nephrotic syndrome as compared with healthy controls. Conclusion s . We found that circulating miR-181a had a significantly different expression and could be an effective means to aid diagnosis of nephrotic syndrome. This microRNA is an attractive candidate as a biomarker for nephrotic syndrome.

/pdf/circulating-micrornas-as-potential-biomarkers-for-nephrotic-1v4mm9u1nt.pdf

Circulating microRNAs as potential biomarkers for nephrotic syndrome.

Single-cell sequencing of PIT1-positive pituitary adenoma highlights the pro-tumour microenvironment mediated by IFN-γ-induced tumour-associated fibroblasts remodelling

Non-functional pituitary adenomas (NFPAs) are one of the most prevalent pituitary adenoma subtypes. The lack of reliable screening approach for NFPAs for the insidious clinical course usually leads to delays in medical therapy and consequently worse prognosis. Hence, we employed a sequence cohort (patient: control, 6:2) and a validation cohort (patient: control, 22:8) to develop a serum exosomal miRNA profile-based method for NFPA screening and prognosis prediction. We found that a total of 1,395 kinds of human miRNA were detected. Compared with healthy donors, 18 up-regulated and 36 down-regulated miRNAs showed significant expression alterations in NFPA patients. Target genes of differentially expressed miRNAs are mainly enriched in axonogenesis and cancer-associated terms. After validation, hsa-miR-486-5p, hsa-miR-151a-5p, hsa-miR-652-3p_R+1, and hsa-miR-1180-3p were promising biomarkers for NFPA, in which miR-486-5p was the most competent one. After a median of 33 months of prospective follow-up, exosomal hsa-miR-486-5p also was an efficient predictive biomarker for progression or relapse of NFPAs. By protein-protein interaction network construction of hsa-miR-486-5p targeted genes, the core modules revealed a high possibility that exosomal hsa-miR-486-5p regulated tumor progression by epigenetic regulation of MAPK signaling pathways. In conclusion, exosomal hsa-miR-486-5p, hsa-miR-151a-5p, hsa-miR-652-3p_R+1, and hsa-miR-1180-3p are candidate biomarkers for diagnosis and screening of NFPAs. More importantly, prospective follow-up reveals that hsa-miR-486-5p can be regarded as a significant predictor for prognosis of NFPAs.

/pdf/exosomal-mirna-profiling-is-a-potential-screening-route-for-2mukzdub.pdf

Exosomal miRNA Profiling is a Potential Screening Route for Non-Functional Pituitary Adenoma

Background Mesangial proliferative glomerulonephritis (MePGN) is characterized by excessive mesangial cell proliferation and mesangial matrix expansion, which lead to glomerular sclerosis and obliteration and, in turn, to deteriorating renal function. To identify and quantify the total proteins in renal tissues of MePGN patients, we used isobaric tags for relative and absolute quantification (iTRAQ) technology, and then looked for differentially expressed proteome profiles in MePGN patients. Methods Eight-plex iTRAQ coupled with multiple chromatographic fractionation and tandem mass spectrometry was used to analyze total proteins in renal tissues of MePGN patients. Proteins were identified using Mascot, compared to show any differential expression. Results Among 512 distinct proteins identified, 113 proteins were up-regulated or down-regulated with a onefold or more alteration in levels across groups. Among of them, there was significant variation in our present iTRAQ study, which contains lamin A, actin, profilin-1, annexin-A1 and A2 up-regulated, and antiquitin and aldolase B down-regulated. Conclusion iTRAQ-based quantitative proteomic technology is efficiently applicable for protein identification and relative quantitation of proteomes of renal tissue. Differentially expressed proteome profiles of MePGN patients are determined. Further investigation of the molecular mechanism of the involved proteins may help to better understand the pathogenesis of MePGN and to discover novel biomarker candidates, which may enable the development of new approaches to diagnosis of MePGN.

Differential proteomic analysis of renal tissue in mesangial proliferative glomerulonephritis using iTRAQ technology.

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Circulating microRNAs as potential biomarkers for nephrotic syndrome.

Single-cell sequencing of PIT1-positive pituitary adenoma highlights the pro-tumour microenvironment mediated by IFN-γ-induced tumour-associated fibroblasts remodelling

Exosomal miRNA Profiling is a Potential Screening Route for Non-Functional Pituitary Adenoma

Differential proteomic analysis of renal tissue in mesangial proliferative glomerulonephritis using iTRAQ technology.