Therapeutic Evaluation of Rosmarinic Acid in a Rat Model Combining Hypertension, Diabetes, and Nephrolithiasis

Background: Cardiometabolic disorders such as hypertension and diabetes are major contributors to chronic kidney disease and often coexist, amplifying dysfunction and metabolic imbalance that favor renal injury and nephrolithiasis. Although pharmacological therapies exist for blood pressure and glycemic control, few target these mechanisms simultaneously. Rosmarinic acid (RA), a polyphenolic compound, exhibits antioxidant, anti-inflammatory, and nephroprotective effects, but its role in combined models of hypertension, diabetes, and nephrolithiasis remains unexplored. Objectives: This study investigated the therapeutic potential of RA in an experimental model combining hypertension, diabetes mellitus, and nephrolithiasis. Methods: Male Wistar spontaneously hypertensive (SHR) and normotensive rats were assigned to eight groups, including controls, comorbid groups, and treatments with RA (10 mg/kg) or hydrochlorothiazide (HCTZ; 5 mg/kg). Diabetes was induced by streptozotocin and nephrolithiasis by ethylene glycol plus ammonium chloride. Hemodynamic, biochemical, oxidative stress, and histological parameters were assessed. Results: SHR exhibited sustained hypertension, further aggravated by diabetes and nephrolithiasis. RA stabilized arterial pressure progression, whereas HCTZ significantly reduced blood pressure. RA and HCTZ treatments decreased urinary calcium oxalate crystal formation by 47.34 and 58.99%, respectively, and partially restored renal morphology. RA restored superoxide dismutase activity, preserved nitrite levels, and reduced lipid peroxidation, indicating antioxidant and endothelial protection. Neither treatment normalized glycemia or fully recovered renal function. Histological analysis showed attenuation of tubular and glomerular alterations in treated groups, particularly with RA. Conclusions: Overall, RA exerted antioxidant, nephroprotective, and antilithogenic effects in this complex comorbidity model, supporting its potential as a complementary therapeutic agent in chronic metabolic and renal disorders.