Periostin Contributes to Immunoglobulin a Nephropathy by Promoting the Proliferation of Mesangial Cells: A Weighted Gene Correlation Network Analysis

Abstract

Immunoglobulin A nephropathy (IgAN) is a known cause of end-stage kidney disease, but the pathogenesis and factors affecting prognosis are not fully understood. In the present study, we carried out weighted gene correlation network analysis (WGCNA) to identify hub genes related to the occurrence of IgAN and validated candidate genes in experiments using mouse mesangial cells (MMCs) and clinical specimens (kidney tissue from IgAN patients and healthy controls). We screened the GSE37460 and GSE104948 differentially expressed genes common to both datasets and identified periostin (POSTN) as one of the five key genes using the cytoHubba plugin of Cytoscape software and by receiver-operating characteristic curve analysis. The top 25% of genes in the GSE93798 dataset showing variable expression between IgAN and healthy tissue were assessed by WGCNA. The royalblue module in WGCNA was closely related to creatinine and estimated glomerular filtration rate (eGFR) in IgAN patients. POSTN had very high module membership and gene significance values for creatinine (0.82 and 0.66, respectively) and eGFR (0.82 and −0.67, respectively), indicating that it is a co-hub gene. In MMCs, POSTN was upregulated by transforming growth factor β1, and stimulation of MMCs with recombinant POSTN protein resulted in an increase in the level of proliferating cell nuclear antigen (PCNA) and a decrease in that of B cell lymphoma-associated X protein, which were accompanied by enhanced MMC proliferation. POSTN gene knockdown had the opposite effects. Immunohistochemical analysis of kidney tissue specimens showed that POSTN and PCNA levels were elevated, whereas the rate of apoptosis was reduced in IgAN patients relative to healthy controls. POSTN level in the kidney tissue of IgAN patients was positively correlated with creatinine level and negatively correlated with eGFR. Thus, POSTN promotes the proliferation of MCs to promote renal dysfunction in IgAN.

Systematic identification of key extracellular proteins as the potential biomarkers in lupus nephritis

“…As a member of the collagen family, COL1A2 is significantly upregulated in metastatic ccRCC ( 42 ). Moreover, periostin (POSTN) has been identified as one of key genes and is significantly upregulated in IgA nephropathy (IgAN) with enhancing mesangial cell proliferation ( 43 ).…”

Identification and external validation of the hub genes associated with cardiorenal syndrome through time-series and network analyses

“…Cardiofibrosis has a significant influence on the prognosis of heart diseases, which can be regulated by POSTN [ 47 , 48 ]. POSTN was also found to be associated with renal diseases, including diabetic kidney disease [ 49 ], immunoglobulin A nephropathy [ 50 ], and polycystic kidney disease [ 51 ]. Hence, regardless of the absence of a regulatory relationship of POSTN and FN1 with CRS, FN1 and POSTN may exert important biological functions in the pathogenesis of CRS.…”

Periostin as a Biomarker in the Setting of Glomerular Diseases—A Review of the Current Literature

“…The Polish research group of Mizerska-Wasiak et al failed to replicate the previously mentioned results of Hwang et al [ 51 ], but their analysis of a 20 patient cohort with IgAN may have been confounded by the fact that the analysis was performed in a pediatric population (3 to 17 year old subjects), by the lack of measurement of urinary periostin at baseline (kidney biopsy moment), and by the fact that the subjects had low severity CKD stage G1 to G2 [ 54 ]. New data support the fact that periostin acts directly on the mesangial cell, as exogenous administration of periostin led to an increase in proliferating cell nuclear antigen (PCNA) with downstream enhancing of mesangial cell proliferation; its expression in kidney tissue was also correlated with serum creatinine levels and eGFR [ 55 ].…”