ObjectiveTo identify differentially expressed genes (DEGs) associated with diabetic nephropathy and explore their effects on glomerular podocyte senescence.MethodsRenal tissue transcriptome datasets (GSE142025 and GSE199838) were downloaded from the Gene Expression Omnibus (GEO) database, including 39 renal biopsy specimens from patients with diabetic nephropathy and 24 control specimens. The DESeq2 package in R was used to analyze the data, with P ResultsA total of 180 DEGs were identified (89 upregulated, 91 downregulated) in the 39 diabetic nephropathy and 24 control specimens from the GSE142025 and GSE199838 datasets. KEGG analysis showed significant enrichment of these genes in multiple senescence-related signaling pathways, including the MAPK, Rap1, FoxO, and p53 pathways. Validation in the glomerular dataset GSE96804 revealed that FGF1, GADD45B, NR4A1, SRF, and PARD6A were downregulated, and IKBKB was upregulated in the glomeruli of diabetic nephropathy patients, consistent with the previous datasets; the remaining five genes showed no significant changes. In the mouse model, Fgf1 expression was significantly downregulated in renal tissue, while Gadd45b, Nr4a1, Srf, and Ikbkb were upregulated; Pard6a showed no significant difference. In cell models, Fgf1 was downregulated under high glucose, while Ikbkb showed no significant change. Overexpression of Fgf1 in mouse podocytes suppressed the expression of senescence-related genes p21 and p16 and reduced the DNA damage marker γ-H2AX, whereas Fgf1 knockdown had the opposite effect. In vivo, rFgf1 treatment inhibited STZ-induced glomerular extracellular matrix accumulation, reduced glomerular SA-β-gal activity, and lowered the expression of p16, p21, and γ-H2AX in renal tissue and podocytes, thereby ameliorating podocyte senescence and diabetic nephropathy progression.ConclusionFgf1 is downregulated in renal tissue, glomeruli, and high glucose-induced podocytes in diabetic nephropathy, and Fgf1 alleviates the progression of diabetic nephropathy in mice by inhibiting glomerular podocyte senescence.
LI et al. (Wed,) studied this question.