Single Nucleotide Polymorphisms of IL-33 Gene Correlated with Renal Allograft Fibrosis in Kidney Transplant Recipients

Abstract

Background. Nowadays, renal allograft survival is confined by the development of allograft fibrosis. Previous studies have reported interleukin-33 (IL-33) upregulated significantly in patients with chronic renal allograft dysfunction, and it could induce renal tubular epithelial to mesenchymal transition (EMT), which eventually contributed to renal allograft fibrosis. Our study intended to detect the underlying association between single nucleotide polymorphisms (SNPs) of IL-33 gene and renal allograft fibrosis in kidney transplant recipients. Methods. We collected blood samples from 200 renal transplant recipients for the identification of SNPs and transplanted kidney tissue samples for identifying differentially expressed genes (DEGs). Intersection of SNP-related genes and DEGs was conducted for further analysis. Relationships between these SNPs and renal allograft fibrosis were evaluated by the inheritance models. Immunohistochemical (IHC) staining and western blotting (WB) were used to detect the expression of IL-33 and the markers of EMT in human kidney tissues obtained from control and chronic renal allograft dysfunction (CAD) patients. In vitro, we detected the progressions of EMT-related markers and the levels of MAPK signaling pathway mediators after transfecting IL-33 mutant plasmids in HK2 cells. Results. Three intersected genes including IL-33 genes were significantly expressed. IL-33 expression was validated in kidney tissues by IHC and WB. Thirty-nine IL-33-related SNPs were identified in targeted sequencing, in which 26 tagger SNPs were found by linkage disequilibrium analysis for further analysis. General linear models indicated sirolimus administration significantly influenced renal allograft fibrosis ( P < 0.05 ), adjustment of which was conducted in the following analysis. By multiple inheritance model analyses, SNP rs10975519 of IL-33 gene was found closely related to renal allograft fibrosis ( P < 0.005 ). Furthermore, HK2 cells transfected with mutated plasmid of rs10975519 showed stronger mobility and migration ability. Moreover, IL-33 mutant plasmids could promote the IL-33-induced EMT through the sustained activation of p38 MAPK signaling pathway in HK2 cells. Conclusion. In our study, rs10975519 on the IL-33 gene was found to be statistically associated with the development of renal allograft fibrosis in kidney transplant recipients. This process may be related to the IL-33-induced EMT and sustained activation of p38 MAPK signaling pathway.

Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease

“…In the context of the kidney, IL-33 has been implicated in the development and progression of several diseases etiologies, including acute kidney injury, CKD, glomerulonephritis, and renal allograft fibrosis. 38 , 40 , 50 , 74 , 75 , 76 , 77 , 78 In several mouse models of renal disease, blocking IL-33 has also been shown to reduce disease severity. 74 , 75 , 79 , 80 , 81 Our investigation of IL-33 in DKD has provided additional insight into the important immunomodulatory effect of this alarmin.…”

Single-nucleotide polymorphisms of matrix metalloproteinase genes are associated with graft fibrosis after kidney transplantation

“…In relation to the continuous variables, we included the indicators in a sequential manner in a model that used the adjusted confounding factors based on the relative degree of their connection with allograft fibrosis. In our previous study, the administration of sirolimus was identified as the confounding factor by the GLM analysis, which suggests that sirolimus treatment significantly affects the severity of fibrosis in renal grafts (21). Next, after using the Bonferroni correction to adapt the various sirolimus treatments (adjusted P=0.005), a multiple inheritance model analysis was performed for each of the 5 analytical models (i.e., the dominant, recessive, additive, overdominant, and codominant models) to investigate the association between these MMP tagger SNPs and renal graft fibrosis after kidney transplantation (Table S3).…”

“…of Nanjing Medical University who underwent kidney transplantation from February 2010 to December 2015 were recruited for this study. The inclusion and exclusion criteria were described in our previous related study (21). Medical information, including each recipient's age, sex, weight, demographic details, the cause of the kidney disease, serum creatinine, and human leukocyte antigen (HLA) mismatch, were extracted from hospital records.…”