Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of primary human mesothelial cells reveals gene expression changes in response to fibrogenic stimulation

ABSTRACT: End-stage kidney disease is a growing global health challenge. Kidney replacement options include transplantation, hemodialysis, and peritoneal dialysis, with the latter being the most rapidly expanding and widely accessible form of dialysis worldwide. Notably, peritoneal fibrosis affects approximately half of all peritoneal dialysis patients and leads to multiple modes of treatment failure, driving the need for better mechanistic understanding and novel therapeutic strategies. In this study, we performed an in-depth analysis of the transcriptomic profiles of primary human mesothelial cells under baseline conditions and after fibrogenic stimulation using RNA-seq. Our findings confirm the suppression of branched-chain amino acid catabolism in a TGF-β1-induced mesothelial-mesenchymal transition model, revealing new potential therapeutic avenues for combating peritoneal fibrosis.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Junhao Dai

PROVIDER: E-MTAB-16003 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Peritoneal dialysis (PD) is the worldwide recognized preferred dialysis treatment for children affected by end-stage kidney disease (ESKD). However, due to the unphysiological composition of PD fluids, the peritoneal membrane (PM) of these patients may undergo structural and functional alterations, which may cause fibrosis. Several factors may accelerate this process and primary kidney disease may have a causative role. In particular, patients affected by corticoresistant primary focal segmental glomerulosclerosis), a rare glomerular disease leading to nephrotic syndrome and ESKD, seem more prone to develop peritoneal fibrosis. The mechanism causing this predisposition is still unrecognized. To better define this condition, we carried out, for the first time, a new comprehensive comparative proteomic mass spectrometry analysis of mesothelial exosomes from peritoneal dialysis effluent (PDE) of 6 pediatric patients with focal segmental glomerular sclerosis (FSGS) versus 6 patients affected by other primary renal diseases (No FSGS). Our omic study demonstrated that, despite the high overlap in the protein milieu between the two study groups, machine learning allowed a complete distinction of the whole proteomic exosome mesothelial content of FSGS versus No FSGS (with 100% accuracy). Out of the 2490 identified proteins, 40% (995) were involved in epithelial-mesenchymal transition (EMT)/fibrosis and in the transforming growth factor-β pathway. Additionally, the Weight Gene Co-expression Network Analysis algorithm identified that some of the discriminative proteins (TIMP1, CTHRC1, SPARC, CHMP4B, COL5A2, ANXA13, FNC2 and CENP-E) were also highly correlated to PD vintage, fibrosis, EMT and non-neoplastic PM disease. All together our data demonstrated that mesothelial cells of FSGS patients are more prone to activate a pro-fibrotic machinery with exosomes having a primary role in this process. Moreover, they indicated that identified FSGS-associated elements in mesothelial exosome protein could be employed as potential new biomarkers of mesothelial integrity. Finally, our results highlighted that in FSGS patients particular attention should be paid to use more biocompatible dialysis solution, reduce the length of time on PD and personalize PD regimens to minimize the risk of rapid loss of PM function or development of encapsulating peritoneal sclerosis.

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RNA-seq of primary human mesothelial cells reveals gene expression changes in response to fibrogenic stimulation

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