SGLT2 inhibitors and NLRP3 inflammasome: potential target in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease (CKD) worldwide. The pathogenesis of DKD is influenced by functional, histopathological, and immune mechanisms, including NLRP3 inflammasome activity and oxidative stress. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown metabolic benefits and the ability to slow the progression of DKD in several clinical studies over the years. Recent studies suggest that the antidiabetic activity also extends to inhibition of the inflammatory response, including modulation of the NLRP3 inflammasome, reduction of pro-inflammatory markers and reduction of oxidative stress. Here we review the efficacy of SGLT2i in the treatment of CKD and discuss the role of the inflammatory response in the development of DKD, including its relationship to the NLRP3 inflammasome and oxidative stress.

Figure 1. NLRP3 inflammasome activation and the possible mechanisms of action of SGLT2i. The NLRP3 inflammasome activation relies on two key mechanisms. Firstly, NF-kB activation in the nucleus prompts the transcription of pro-IL-1β, pro-IL-18, and NLRP3 enzyme. Subsequently, a secondary signal triggers NLRP3 complex activation through cleavage of pre-activated precursors by stimuli like DAMPs or increased ROS concentration, leading to cytokine release and pyroptosis. SGLT2i potentially inhibits NF-kB, NLRP3, ASC, and Pro-caspase-1 activities, Gasdermin-D activation, and reduces IL-1β levels and mitochondrial reactive oxygen species (mROS).

Figura 1. Ativação do inflamassoma NLRP3 e os possíveis mecanismos de ação dos iSGLT2. A ativação do inflamassoma NLRP3 depende de dois mecanismos principais. Primeiramente, a ativação do NF-kB no núcleo estimula a transcrição das enzimas pró-IL-1β, pró-IL-18 e NLRP3. Posteriormente, um sinal secundário desencadeia a ativação do complexo NLRP3 por meio da clivagem de precursores pré-ativados por estímulos como DAMPs ou aumento da concentração de EROs, levando à liberação de citocinas e piroptose. Os iSGLT2 inibem potencialmente as atividades de NF-kB, NLRP3, ASC e Pro-caspase-1, a ativação de Gasdermin-D e reduzem os níveis de IL-1β e as espécies reativas de oxigênio mitocondriais (EROm).