The SGLT2 Inhibitor Empagliflozin Mitigates the Harmful Effects of Methylglyoxal Exposure on Ovalbumin-Induced Mouse Airway Inflammation

Author(s)

Medeiros, Matheus L. ; Oliveira, Akila L. ; Antunes, Edson

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 26, n. 12, p. 19-pg., 2025-06-16.

Abstract

Asthma is a chronic inflammatory airway disease that can be aggravated by metabolic comorbidities such as type 2 diabetes mellitus (DM2) and obesity. Elevated levels of methylglyoxal (MGO), a reactive glycolysis byproduct, have been associated with exacerbation of allergic airway disease. SGLT2 inhibitors have been successfully employed in DM2 treatment. Here, we hypothesized that elimination of MGO might be a potential anti-inflammatory mechanism of SGLT2 inhibitors. This study aimed to evaluate the effects of empagliflozin on ovalbumin (OVA)-induced airway inflammation in mice chronically exposed to MGO. Male C57BL/6 mice sensitized with OVA were exposed to 0.5% MGO for 12 weeks and treated with empagliflozin (10 mg/kg, gavage, two weeks). MGO exposure significantly enhanced airway eosinophil infiltration, mucus production and collagen deposition, as well as levels of IL-4, IL-5, eotaxin and TNF-alpha. Empagliflozin treatment significantly reduced OVA-induced airway disease, which was accompanied by reductions in IgE, IL-4, IL-5, eotaxin, and TNF-alpha levels. Empagliflozin significantly reduced the MGO levels in serum, and immunohistochemical staining, and protein expression of MGO-hydroimidazolone (MG-H1), while increasing IL-10 levels and glyoxylase-1 (GLO 1) activity in lungs. In conclusion, empagliflozin efficiently removes MGO from circulation, while increasing the MGO detoxification by GLO 1, thereby mitigating the OVA-induced inflammation in MGO-exposed mice. (AU)

• FAPESP's process: 24/10306-4 - Methylglyoxal - advanced glycation end products (AGEs) - receptor for AGEs (AGEr) axis: A potential therapeutical target for prevention and treatment of bladder dysfunction associated with obesity and diabetes
• Grantee: Edson Antunes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 24/03508-0 - Obesity and asthma: role of methylglyoxal and advanced glycation end products in allergic pulmonary inflammatory response in genetically obese mice
• Grantee: Matheus Leite de Medeiros
• Support Opportunities: Scholarships in Brazil - Post-Doctoral