Diabetic kidney disease (DKD), a microvascular complication of diabetes mellitus, represents a significant clinical challenge. This study investigated the reno-protective effects of dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) widely used in the management of diabetes, and aimed to elucidate its underlying mechanisms. Mice with db/db and db/m genotypes were allocated into four experimental groups and treated with either dulaglutide or a saline control for 10 weeks. Following the treatment period, biological samples were collected for comprehensive analysis. Serum and urinary creatinine levels were measured using a creatinine assay, while urinary protein concentrations were quantified via ELISA. Histopathological kidney damage was assessed through hematoxylin and eosin (HE) staining, with glomerular lesions evaluated using periodic acid-Schiff (PAS) staining. Inflammatory markers, ferroptosis-related indicators, and fibrosis in kidney tissues were further analyzed through PCR, Western blot (WB), immunohistochemistry (IHC), and transmission electron microscopy (TEM). Consistent with prior findings, this research demonstrated that dulaglutide improves renal function and mitigates pathological kidney damage in db/db mice. Treatment with dulaglutide significantly reduced mRNA expression of ferroptosis-related markers, including ACSL4, SLC7A11, and Ptgs2, alongside a decrease in 4-HNE levels in kidney tissues. Furthermore, dulaglutide downregulated ACSL4 protein levels and upregulated GPX4 protein expression, thereby ameliorating mitochondrial damage in renal tubular cells. In addition to these effects, dulaglutide alleviated kidney inflammation and fibrosis in db/db mice, with concomitant suppression of P-STAT3 and P-ERK expression. Collectively, these findings underscore dulaglutide's reno-protective effects in DKD, mediated through the inhibition of inflammation, improvement in renal fibrosis and ferroptosis, and modulation of P-STAT3 and P-ERK signaling pathways.
