Fosinopril ameliorates renal injury in diabetic nephropathy by inactivating the SRC/NF-κB pathway

Diabetic nephropathy (DN) is a serious complication of diabetes, characterized by renal tissue injury. Fosinopril, an ACE inhibitor, has been shown to have renoprotective effects in DN, but the underlying mechanisms are not fully understood. A mouse model of DN was established by administering streptozotocin (STZ) to C57BL/6J mice. The effects of fosinopril on renal tissue injury were assessed by administering the drug orally for 8 weeks. Serum creatinine (Scr) and blood urea nitrogen (BUN) levels were measured through colorimetric methods, and blood glucose levels were determined using a glucometer. Histopathological changes in renal tissues were evaluated using hematoxylin and eosin staining, PAS staining, and Masson’s trichrome staining. HK2 cells were stimulated with high glucose and TGF-β1 to mimic DN-like cell injury. Enzyme-linked immunosorbent assays (ELISAs) were performed to detect levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). TUNEL assay was employed to evaluate cell apoptosis, while colorimetric assays were utilized to determine the levels of malondialdehyde (MDA) and superoxide dismutase (SOD). Reactive oxygen species (ROS) levels were assessed using a fluorometric assay. Cell viability was analyzed by a cell counting kit-8 (CCK-8) assay, and flow cytometry was used to assess cell apoptosis. Network pharmacology analysis was conducted to identify the protein target of fosinopril in DN. Protein expression was detected by western blotting assay. Fosinopril administration effectively mitigated renal injury in STZ-induced DN mice by reducing levels of kidney function and inflammatory markers, improving histological parameters, and normalizing the balance of apoptosis and oxidative stress. Network pharmacology analysis identified SRC as a target of fosinopril in DN. In addition, overexpression of SRC attenuated the inhibitory effects of fosinopril on inflammation, apoptosis, and oxidative stress in HG-induced HK2 cells. Furthermore, fosinopril ameliorated inactivated the NF-κB pathway through the regulation of SRC. These findings suggest that fosinopril may be an effective therapeutic option for the management of DN by inactivating the SRC/NF-κB pathway, which could have significant clinical implications in the treatment of patients with DN.