AUTHOR=Yang Yuan-Yuan , Gao Zhong-Xiuzi , Mao Zi-Hui , Liu Dong-Wei , Liu Zhang-Suo , Wu Peng 

TITLE=Identification of ULK1 as a novel mitophagy-related gene in diabetic nephropathy

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1079465

DOI=10.3389/fendo.2022.1079465

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>Accumulating evidence indicates that mitophagy is crucial for the development of diabetic nephropathy (DN). However, little is known about the key genes involved. The present study is to identify the potential mitophagy-related genes (MRGs) in DN.</p></sec><sec><title>Methods</title><p>Five datasets were obtained from the Gene Expression Omnibus (GEO) database and were split into the training and validation set. Then the differentially expressed MRGs were screened and further analyzed for GO and KEGG enrichment. Next, three algorithms (SVM-RFE, LASSO and RF) were used to identify hub genes. The ROC curves were plotted based on the hub genes. We then used the CIBERSORT algorithm to assess the infiltration of 22 types of immune cells and explore the correlation between hub genes and immune cells. Finally, the Nephroseq V5 tool was used to analyze the correlation between hub genes and GFR in DN patients.</p></sec><sec><title>Results</title><p>Compared with the tubulointerstitium, the expression of MRGs was more noticeably varied in the glomeruli. Twelve DE-MRGs were identified in glomerular samples, of which 11 genes were down-regulated and only <italic>MFN1</italic> was up-regulated. GO and KEGG analysis indicated that several enrichment terms were associated with changes in autophagy. Three genes (<italic>MFN1</italic>, <italic>ULK1</italic> and <italic>PARK2</italic>) were finally determined as potential hub genes by three algorithms. In the training set, the AUROC of <italic>MFN1</italic>, <italic>ULK1</italic> and <italic>PARK2</italic> were 0.839, 0.906 and 0.842. However, the results of the validation set demonstrated that <italic>MFN1</italic> and <italic>PARK2</italic> had no significant difference in distinguishing DN samples from healthy controls, while the AUROC of <italic>ULK1</italic> was 0.894. Immune infiltration analysis using CIBERSORT showed that <italic>ULK1</italic> was positively related to neutrophils, whereas negatively related to M1 and M2 macrophages. Finally, <italic>ULK1</italic> was positively correlated with GFR in Nephroseq database.</p></sec><sec><title>Conclusions</title><p><italic>ULK1</italic> is a potential biomarker for DN and may influence the development of diabetic nephropathy by regulating mitophagy.</p></sec>