Introduction:
Vascular calcification has been proven to be tightly associated with the inhibition of autophagy in the development of diabetes. However, the molecular mechanism of vascular calcification and chaperone-mediated autophagy related genes (VC-CMARGs) in diabetic nephropathy (DN) patients is still vague. The study aimed to explore the relationship between vascular calcification and autophagy in diabetic nephropathy, and to find new therapeutic targets.
Methods:
Firstly, the differentially expressed analysis and weighted gene co-expression network analysis were proceeded to identify the candidate genes for DN based on GSE30529 dataset. Afterwards, the Mendelian randomization analysis was performed to single out the candidate genes causally related to DN. The biomarkers of DN were further acquired according to their expression in GSE30529 training set and GSE96804 validation set, followed by construction of nomogram. Later on, the gene set enrichment analysis, immune infiltration analysis, drug prediction and construction of molecular regulatory network were conducted. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to detect the expression level of biomarkers in DN and normal clinical samples.
Results:
A total of 286 candidate genes were screened out in GSE30529, which mainly involved in humoral immune response, leukocyte mediated immunity and complement and coagulation cascades. Among these candidate genes, seven genes (APOBEC3B, SERPING1, ADCY7, AEBP1, JCHAIN, CLEC2B and IFI44L) were causally relevant to DN development. Only JCHAIN and IFI44L were defined as biomarkers because of their increased expression and risk attribute for DN. Both biomarkers were enriched in immune related functions. Moreover, they were strongly associated with discrepant immune cells (Cor>0.55), such as activated CD4 T cell, mast cell and central memory CD4 T cell. The expression of IFI44L might be mediated by miRNAs (hsa-miR-34b-5p, hsa-miR-124-3p and hsa-miR-146a-5p) and transcription factor YY1. At the last part, we discovered that ethyl methanesulfonate, vincristine and demecolcin might be potential drugs for DN treatment targeting JCHAIN and IFI44L. RT-qPCR revealed increased expression levels of both JCHAIN (P=0.0155) and IFI44L (P=0.0203) in the DN group, consistent with the expression trends in the GSE30529 and GSE96804 datasets.
Conclusions:
Our investigation excavated two VC-CMARGs as biomarkers for DN, namely JCHAIN and IFI44L, which could afford a fresh theoretical reference for clinical diagnosis and treatment of DN patients.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.