Systematic validation of zucker diabetic-sprague dawley male rats as a model for type 2 diabetes-associated diabetic retinopathy

Abstract The Zucker Diabetic Sprague-Dawley (ZDSD) rat is an emerging model for type 2 diabetes, but its suitability for diabetic retinopathy (DR) research remains unvalidated. This study aimed to perform a systematic, multimodal characterization of DR in the ZDSD rats to assess its translational relevance. Male ZDSD rats were fed a high-fat diet to induce diabetes, forming Diabetic and Normoglycemic Control groups ( n = 8 per group), alongside healthy Sprague-Dawley control ( n = 8). Metabolic parameters were monitored from 27 to 36 weeks. Retinal assessment combined in vivo imaging (OCTA, FFA, OCT), histology (H&E staining), and molecular biology (qRT-PCR, Western blot, IHC, ELISA) to quantify key DR mediators: inflammatory factors (TNF-α, IL-1β, IL-6), VEGF, and Caspase-3. Diabetic ZDSD rats exhibited severe hyperglycemia, polydipsia, and weight loss. Retinal imaging revealed significant pathology, including progressive reduction in vascular density (OCTA), retinal thinning (OCT), and microvascular leakage (FFA). Histology confirmed structural disorganization and reduced retinal ganglion cell and photoreceptor density. Molecular analyses demonstrated significant upregulation of retinal inflammatory cytokines, elevated VEGF expression in retinal tissue and aqueous humor, and increased Caspase-3, indicating enhanced apoptosis. The ZDSD rat model reproduces several key metabolic, microvascular, structural, and molecular hallmarks of human non-proliferative DR. These findings support its potential utility as a relevant platform for investigating NPDR pathogenesis and evaluating early-stage therapeutics.