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Identification of mechanistic chronic kidney disease biomarkers by comprehensive bulk RNA-seq transcriptomics and SWATH proteomics of the rat sub-total nephrectomy model of kidney fibrosis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE253009 | GEO | 2025/01/01

REPOSITORIES: GEO

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Identification of mechanistic chronic kidney disease biomarkers by comprehensive bulk RNA-seq transcriptomics and SWATH proteomics of the rat sub-total nephrectomy model of kidney fibrosis [RNA-Seq_1]

Project description:The rat sub-total nephrectomy (SNx) is a functional model of chronic kidney disease (CKD), where the main pathological driver is glomerular hypertension. Comprehensive transcriptomics and proteomics analyses on the rat SNx model were performed to identify biomarkers in plasma or urine that correlate with kidney disease and functional kidney loss. Kidneys were subjected to collagen I and III staining for fibrosis scoring, SWATH proteomics and bulk RNA-sequencing transcriptomics (RNA-seq), with SWATH also performed on plasma and urine. Differential expression analysis demonstrated significant dysregulation of genes and proteins involved in fibrosis, metabolism, and immune response in the SNx rats compared to controls. Gene ontology analysis of the intersecting genes and proteins from both studies demonstrated common biology between animal cohorts that reached the predefined kidney disease thresholds (serum creatinine >2-fold or proteinuria >3-fold increase over sham-operated). Thirteen significantly differential molecules were detected with consistent directional changes in both transcriptomics and proteomics datasets. These molecules were detected independently in kidney (both RNA and protein) and urine (protein only), but not in plasma. The bioinformatics analysis enabled the identification of mechanistic CKD biomarkers including lumican and collagen alpha-1(III) chain, whose co-expression has previously been both implicated in fibrosis and detected in urine in CKD patients.

2025-01-01 | GSE253007 | GEO

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Identification of mechanistic chronic kidney disease biomarkers by comprehensive bulk RNA-seq transcriptomics and SWATH proteomics of the rat sub-total nephrectomy model of kidney fibrosis

Project description:Identification of mechanistic chronic kidney disease biomarkers by comprehensive bulk RNA-seq transcriptomics and SWATH proteomics of the rat sub-total nephrectomy model of kidney fibrosis

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Biomarkers in kidney fibrosis: are they useful?

Project description:With the escalating cost of monitoring and follow-up required in the care of patients with chronic kidney disease (CKD), biomarkers are increasingly being investigated for their utility in predicting patients most at risk of decline in renal function in order to rationalize and target care. Putative biomarkers have also emerged as treatment targets, with the potential to develop novel therapeutics. However, biomarker studies in CKD are largely derived from single-sample collections in observational or nested case-control studies that are suboptimal in study design, analyses, and end points relevant to confirm the utility of specific biomarkers. It has been demonstrated that biomarker expression may be modified by declining kidney function. Hence, their value in predicting future kidney dysfunction is limited. Therefore, understanding the nature, mechanism of action, and how specific biomarkers interact with the CKD disease process is a crucial step in defining the potential for biomarkers to predict outcome, or alternatively, develop as a therapeutic target. Unlike conventional risk factors that, albeit partly, enable us to distinguish an individual at risk of cardiovascular disease, biomarkers in patients with CKD may not be required to be modifiable either directly or indirectly in the disease process or by therapy. Reproducibility and prospective validation remain major challenges for the burgeoning number of purported biomarkers in patients with CKD. It is highly likely a combination of conventional and novel biomarkers will be needed to accurately predict the risk of end-stage kidney disease. This review will focus on recently identified biomarkers and their utility in predicting progressive kidney fibrosis.

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Comprehensive Proteomics Profiling Reveals Circulating Biomarkers of Hypertrophic Cardiomyopathy.

Project description:BackgroundHypertrophic cardiomyopathy (HCM) is caused by mutations in the genes coding for proteins essential in normal myocardial contraction. However, it remains unclear through which molecular pathways gene mutations mediate the development of HCM. The objectives were to determine plasma protein biomarkers of HCM and to reveal molecular pathways differentially regulated in HCM.MethodsWe conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma proteomics profiling of 1681 proteins. We performed a sparse partial least squares discriminant analysis to develop a proteomics-based discrimination model with data from 1 institution (ie, the training set). We tested the discriminative ability in independent samples from the other institution (ie, the test set). As an exploratory analysis, we executed pathway analysis of significantly dysregulated proteins. Pathways with false discovery rate <0.05 were declared positive.ResultsThe study included 266 cases and 167 controls (n=308 in the training set; n=125 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83-0.94) in the test set. Pathway analysis revealed that the Ras-MAPK (mitogen-activated protein kinase) pathway, along with its upstream and downstream pathways, was upregulated in HCM. Pathways involved in inflammation and fibrosis-for example, the TGF (transforming growth factor)-β pathway-were also upregulated.ConclusionsThis study serves as the largest-scale investigation with the most comprehensive proteomics profiling in HCM, revealing circulating biomarkers and exhibiting both novel (eg, Ras-MAPK) and known (eg, TGF-β) pathways differentially regulated in HCM.

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Comprehensive bulk RNAseq analysis on whole kidneys during regeneration and fibrosis development reveals sustained dysregulation of immune system related pathways during kidney fibrosis

Project description:In order to identify the transcriptional changes that correlate with kidney regeneration or fibrosis development, we performed a time-course bulk RNA-seq from whole-kidneys at 3, 7, 14, 28 and 42 days after the initial ischemic kidney from two distinct murine models.

2020-01-31 | E-MTAB-7957 | biostudies-arrayexpress

iTRAQ-Based Proteomics Reveals Novel Biomarkers for Idiopathic Pulmonary Fibrosis.

Project description:Idiopathic pulmonary fibrosis (IPF) is a gradual lung disease with a survival of less than 5 years post-diagnosis for most patients. Poor molecular description of IPF has led to unsatisfactory interpretation of the pathogenesis of this disease, resulting in the lack of successful treatments. The objective of this study was to discover novel noninvasive biomarkers for the diagnosis of IPF. We employed a coupled isobaric tag for relative and absolute quantitation (iTRAQ)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach to examine protein expression in patients with IPF. A total of 97 differentially expressed proteins (38 upregulated proteins and 59 downregulated proteins) were identified in the serum of IPF patients. Using String software, a regulatory network containing 87 nodes and 244 edges was built, and the functional enrichment showed that differentially expressed proteins were predominantly involved in protein activation cascade, regulation of response to wounding and extracellular components. A set of three most significantly upregulated proteins (HBB, CRP and SERPINA1) and four most significantly downregulated proteins (APOA2, AHSG, KNG1 and AMBP) were selected for validation in an independent cohort of IPF and other lung diseases using ELISA test. The results confirmed the iTRAQ profiling results and AHSG, AMBP, CRP and KNG1 were found as specific IPF biomarkers. ROC analysis indicated the diagnosis potential of the validated biomarkers. The findings of this study will contribute in understanding the pathogenesis of IPF and facilitate the development of therapeutic targets.

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RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis.

Project description:CKD is the gradual, asymptomatic loss of kidney function, but current tests only identify CKD when significant loss has already happened. Several potential biomarkers of CKD have been reported, but none have been approved for preclinical or clinical use. Using RNA sequencing in a mouse model of folic acid-induced nephropathy, we identified ten genes that track kidney fibrosis development, the common pathologic finding in patients with CKD. The gene expression of all ten candidates was confirmed to be significantly higher (approximately ten- to 150-fold) in three well established, mechanistically distinct mouse models of kidney fibrosis than in models of nonfibrotic AKI. Protein expression of these genes was also high in the folic acid model and in patients with biopsy-proven kidney fibrosis. mRNA expression of the ten genes increased with increasing severity of kidney fibrosis, decreased in response to therapeutic intervention, and increased only modestly (approximately two- to five-fold) with liver fibrosis in mice and humans, demonstrating specificity for kidney fibrosis. Using targeted selected reaction monitoring mass spectrometry, we detected three of the ten candidates in human urine: cadherin 11 (CDH11), macrophage mannose receptor C1 (MRC1), and phospholipid transfer protein (PLTP). Furthermore, urinary levels of each of these three proteins distinguished patients with CKD (n=53) from healthy individuals (n=53; P<0.05). In summary, we report the identification of urinary CDH11, MRC1, and PLTP as novel noninvasive biomarkers of CKD.

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