Uncovering the Nephroprotective Mechanism of Caffeic Acid in Renal Tubulointerstitial Fibrosis through Network Pharmacology Analysis

Background: Renal tubulointerstitial fibrosis (RTF) is a progressive kidney condition characterized by the formation of fibrotic tissue. Caffeic acid (CA), a key component of the medicinal plant Antirhea borbonica, shows promise as a potential treatment for renal fibrosis. Here, we investigated the nephroprotective effect of CA in RTF and its underlying mechanisms. Methods: RTF was induced in rats through unilateral ureteral obstruction (UUO), followed by intraperitoneal administration of CA for 5 days. We assessed kidney weight/body weight (KW/BW) ratio, serum creatinine (Scr), blood urea nitrogen (BUN), 24-h urine protein (UP), and performed histological examinations. We also analyzed the expression of fibrosis-related proteins. Genes associated with RTF and CA were identified using public databases. A protein-protein interaction (PPI) network and molecular docking studies were conducted. Results: CA treatment significantly reduced the KW/BW ratio, levels of Scr, BUN, and 24-h UP, indicating improved kidney function in UUO-induced RTF rats. Histological examination revealed reduced fibrotic changes. CA administration also led to decreased collagen deposition and downregulation of fibrosis-related protein expression. CA administration also led to decreased collagen deposition and downregulation of fibrosis-related protein expression. The PPI network analysis showed significant differential expression of 13 genes between the fibrosis and normal groups. Notably, EGFR and MAPK14 were strongly associated with CA, and CA treatment downregulated EGFR and MAPK14 protein expression in UUO rats. Conclusion: CA exhibits substantial nephroprotective effects in UUO-induced RTF rats by modulating key genes EGFR and MAPK14, and MAPK signaling pathway.