DN affects millions of people all over the world30. DN occurs when the uncontrolled diabetes, which is a worldwide complaint. The aim of this investigation was to screen and verify hub genes involved in DN as well as to explore potential molecular mechanisms.
In the present study, NGS data from GSE142025 was extracted to identify the DEGs between DN and normal control. In this investigation, we identified 549 DEGs, which includes 275 up regulated and 274 down regulated genes. CFHR131 and RGS132 have been reported to altered expression in nephropathy. Studies have showed that GREM1 is linked with progression of DN33. Existing evidence has reported that CCL1934 is responsible for renal inflammation and fibrosis in DN. COL6A535 is associated with neuropathic chronic itch. Reports indicate that CIDEC (cell death inducing DFFA like effector c)36 was found in progression of obesity. NR4A1 drives DN growth through mitochondrial fission and mitophagy37. Recent study has reported that expression of NR4A2 is associated with myocardial infarction38. EGR1 is required for fibrosis and inflammatory response in DN39. ATF3 expression has been implicated in DN40. Altered expression of NR4A3 contribute to type 2 diabetes mellitus progression41. A previous study showed that KLK1 gene is involved in DN42.
A series of DEGs were discovered to be enriched in the GO functions and pathways. Previous investigation have shown a signaling pathway includes innate immune system43, extracellular matrix organization44, hemostasis45, cytokine signaling in immune system46 and metabolism of proteins47 were associated with DN development. Previous studies had reported that expression of SERPINA348, IKZF149, BTK (Bruton tyrosine kinase)50, C1QA51, CD1C52 and CCL1353 were correlated with lupus nephritis. Recent studies have demonstrated that expression of TNFSF1454, ITGAL (integrin subunit alpha L)55, PLAC856, ADRA2A57, CCL2158, ALOX559, CNR260, COL1A161, WNT7A62, SLAMF163, CD3D64, LTF (lactotransferrin)65, MIR27B66, PDK467, UCN368, PCK169, CEL (carboxyl ester lipase)70, TRPM671, MTTP (microsomal triglyceride transfer protein)72, CYP2C873 and CYP3A474 are associated with progression of type 2 diabetes mellitus. Recent studies have proposed that the altered expression of MZB175, LAIR176, MIR14277 and FAP (fibroblast activation protein alpha)78 have been shown to be a meaningful advance factor for myocardial infarction. IRF4 plays a key role in the obesity-induced insulin resistance79. Accumulating evidence showed that altered expression of genes such as MDK (midkine)80, CCR281, SAA182, C383, CD1984, CCR585, CXCR386, FABP487, GDF1588, IGF289, IGFBP190 and IL691 are important in the progression of DN. A previous study has shown that UBASH3A92, SIRPG (signal regulatory protein gamma)93, IKZF394, CD1D95, CD296, CD4897, CD24798 and CYP27B199 are liable for progression of type 1 diabetes mellitus. The studies have shown that expression of SIT1100, JAML (junction adhesion molecule like)101, TIMP1102, PRKCB (protein kinase C beta)103, MMP7104, WNT7B105, WNT10A106, DUSP1107, WT1108, APOC3109, ERRFI1110, HCN2111, MME (membrane metalloendopeptidase)112, STRA6113, SLC12A3114 and GC (GC vitamin D binding protein)115 expedites epithelial to mesenchymal transition and renal fibrosis in DN. Previous studies have found CFD (complement factor D)116, DOCK2117, LYZ (lysozyme)118, CD5L119, SCARA5120, VCAN (versican)121, GDF5122, SFRP2123, BTG2124, ZFP36125, GPR3126, OLR1127, PM20D1128 and UGT2B7129 to be expressed in obesity. A study has confirmed that altered expression of FCRL3130, FCGR2B131, COMP (cartilage oligomeric matrix protein)132, ERFE (erythroferrone)133 and NPHS1134 are involved in progression of nephropathy. The expression of COL1A2135, LCK (LCK proto-oncogene, Src family tyrosine kinase)136, LCN2137 and APOB (apolipoprotein B)138 are key for progression of diabetic retinopathy. Researchers showed that altered expression of COL3A1139, PER1140, JUN (Jun proto-oncogene, AP-1 transcription factor subunit)141, SLC26A4142, F2RL3143, CYP4A11144 and CYP4F2145 play an important role in the hypertension. Collectively, results of enriched GO and REACTOME pathway enrichment analysis were positively correlated with experimental findings. However, further investigations are needed to explore and confirm the potentially significant pathways for DN and to achieve a comprehensive understanding of this process.
Based on the PPI network and module analysis, we obtained top hub genes in the whole network. ALB (albumin)146 has been shown as a promising biomarker in DN. In our study, correlations of MDFI (MyoD family inhibitor) and FOS (Fos proto-oncogene, AP-1 transcription factor subunit) with patient prognosis highlight the importance of these genes as novel biomarkers to stratify DN patients as well as potential therapeutic targets, but concrete roles of these genes need further investigation.
Based on the miRNA-DEG regulatory network and TF-DEG regulatory network, we obtained target in the whole network. Recent investigation reported that the altered expression of MYBL2 was associated with myocardial infarction progression147, but this gene might be novel target for DN. Many investigation have reported that expression of hsa-mir-637148 and NR3C1149 were linked with progression of hypertension, but these genes might be novel target for DN. Hsa-mir-1261150 has been shown to have an important role in DN. Hsa-mir-4458151 has been found to be differentially expressed in myocardial infarction, but this gene might be novel target for DN. The recent studies have reported that expression of NFATC2152, PDX1153 and CREB1154 were involved in the progression of type 2 diabetes, but these genes might be novel target for DN. Previous studies have demonstrated that expression of YY1155, TP53156 and SRF (serum-response factor)157 played a key role in progression of DN. IL2RB, hsa-mir-4492, hsa-mir-4319, hsa-mir-4300, hsa-mir-3943, hsa-mir-548e-3p, hsa-mir-6077, hsa-mir-5586-5p, RET (ret proto-oncogene), MAP1LC3C, PTPRO (protein tyrosine phosphatase receptor type O), NR2C2, MAX (myc-associated factor X) and ARID3A might be novel diagnostic biomarkers associated with the progression of DN, which remains to be verified based on a larger sample.
Besides, this investigation is purely a bioinformatics analysis without any in vivo and in vitro data. There are some limitations in our investigation. The lack of molecular and cellular evidences in wet-lab experiment imposes restrictions on the conclusions that can be drawn from our results.