Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Dynamic multi-omics and mechanistic modeling approach uncovers novel mechanisms of kidney fibrosis progression

ABSTRACT: Kidney fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. Aimed at unraveling disease mechanisms and identifying potential therapeutic targets, this study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFRβ+ mesenchymal cells. Using computational network modeling we integrated transcriptomics, proteomics, phosphoproteomics, and secretomics with imaging of the extracellular matrix (ECM). We quantified over 14,000 biomolecules across seven time points following TGF-β stimulation, revealing distinct temporal patterns in the expression and activity of known and potential novel renal fibrosis markers and modulators. The resulting time-resolved multi-omic network models allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and elucidated regulatory mechanisms underlying kidney fibrosis. Notably, we demonstrate that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a valuable resource for the organ fibrosis research community.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Mira Burtscher

PROVIDER: E-MTAB-14521 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:A deletion mutation in the growth hormone receptor (GHR) gene results in the inhibition of skeletal muscle growth and fat deposition in dwarf chickens. In this study, microarray techniques were used to detect the miRNA and mRNA expression profiles of 14-day-old embryo and 7-week-old chicken skeletal muscle of deletion-type dwarf chickens and normal-type chickens. Skeletal muscle tissues of Dwarf recessive White Rock chickens and normal recessive White Rock chickens were used to make the microarray assay. Results show the expression of miR-1623 and miR-181b in 14-day-old embryos and of let-7b and miR-128 in 7-week-old chickens. let-7b was the only miRNA found to be completely complementary to its target in the 3'UTR of GHR and inhibited GHR gene expression. KEGG (Kyoto Encyclopaedia of Genes and Genomes) pathway analysis and RT-PCR verified that there were three main signalling pathways regulating the skeletal muscle growth and fat deposition of chickens influenced by the let-7b-regulated GHR gene. The suppression of the cytokine signalling 3 (SOCS3) gene was found to be involved in the signalling pathway of adipocytokines. We found that let-7b is the critical miRNA involved in the regulation of the GHR gene. SOCS3 plays a critical role in the network regulating skeletal muscle growth and fat deposition via let-7b-mediated GHR gene expression. Two groups were analyzed in the array assay: one group consisted of normal recessive White Rock 14-day-old embryo leg muscle tissues, and the other group consisted of dwarf recessive White Rock 14-day-old embryo leg muscle tissues. The control samples were labeled as A1, A2, A3, and the dwarf chicken samples were labeled as B1, B2, and B3. 9 total embryos per breed, 3 embryos used per breed for each sample. 523 mature miRNA sequences were assembled and integrated into the LC miRNA microarray design, and different expression miRNAs were measured on the 7000HT Fast Real-Time PCR system. This submission represents the miRNA profiling component of the study.

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Dynamic multi-omics and mechanistic modeling approach uncovers novel mechanisms of kidney fibrosis progression

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