SOCS1 Mimetic Peptide Enhances Empagliflozin Improvement on Kidney Damage in the Type 2 Diabetes Mouse Model BTBR ob/ob

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. During the last few years, remarkable advances have been made in the treatment of DN. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) consistently prevent or delay albuminuria and renal failure in patients with DN. Prior research from our group highlights the Janus kinase/signal transducers and activators of transcription axis as a critical target in DN. Specifically, the administration of suppression of cytokine signaling 1 (SOCS1) mimetic peptides (MiS1) modulates aberrant signaling, resulting in profound beneficial effects on renal function and structural integrity in experimental DN. The aim of this study was to evaluate the effect of empagliflozin and MiS1 on kidney damage and its associated inflammatory, oxidative stress and lipotoxic mechanisms in an advanced type 2 DN mouse model BTBR ob/ob. Mice were treated for 7 weeks with empagliflozin and MiS1, alone or in combination, and monitored for glycemia, body weight, albuminuria, histopathological damage, podocyte loss, and gene expression related to inflammation, redox balance, and lipid metabolism. Empagliflozin or MiS1 monotherapies significantly reduced albuminuria and structural renal injury, preserved podocyte number, and downregulated genes involved in inflammatory, oxidative, and mitochondrial-lipid metabolic dysregulation, with empagliflozin additionally improving metabolic parameters. Notably, the combined therapy achieved the greatest reduction in albuminuria and histological damage with enhanced suppression of pathogenic inflammatory and metabolic pathways, resulting in superior renoprotection compared with monotherapy. These findings suggested that add-on therapy with SOCS1 peptidomimetics and SGLT2i may help mitigate residual albuminuria and renal damage in type 2 DN.