Nascent shifts in renal cellular metabolism, structure, and function due to chronic empagliflozin in pre-diabetic mice (https://doi.org/10.1152/ajpcell.00446.2023)
by Blythe D. Shepard, et al. 04 MAR 2024
Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i), particularly empagliflozin, are identified as promising agents for the treatment of type 2 diabetes (T2D) with additional benefits for renal protection beyond glucose reduction. The research focuses on assessing the impact of empagliflozin on renal metabolism and function within a metabolic syndrome model that is pre-diabetic, utilizing both male and female TallyHo (TH) mice alongside their genetically closest lean strain (Swiss-Webster, SW). These subjects were administered a high-milk-fat diet, with or without empagliflozin, for a duration of 12 weeks.
Findings from the study indicate that empagliflozin marginally increased kidney weights and the glomerular filtration rate, specifically in the TH mice population. Through unsupervised clustering of glomerular features, a distinction was noted in the response between genders, alongside a unique cluster associated with empagliflozin treatment. Furthermore, a slight reduction in Periodic acid Schiff (PAS) positive areas, indicative of glycogen storage, was observed with empagliflozin administration. Additional analyses, such as phasor-fluorescent lifetime imaging (FLIM), suggested an enhanced reliance on oxidative phosphorylation for energy within the kidney cortex due to empagliflozin.
Examination of renal function revealed a slight increase in the excretion of sodium, glucose, and albumin in the urine following empagliflozin treatment. Profiling of sodium transporters and channels demonstrated a decrease in sodium phosphate cotransporter, type 2 (NaPi-2), and a minor increase in γ-ENaC associated with the collecting duct, suggesting a shift in sodium reabsorption towards the distal segments of the nephron. The observed microalbuminuria could be indicative of changes in protein reabsorption rather than filtration.
Moreover, a significant alteration in the urine exosomal microRNA profile was evident after empagliflozin treatment. Network analysis of these changes highlighted “cancer pathways” and “FOXO signaling” as predominantly regulated pathways. In conclusion, this paper presents evidence that empagliflozin treatment in pre-diabetic mice with minimal renal disease initiates changes in renal metabolism, potentially offering a protective mechanism against kidney disease in the progression of T2D.
Uthando Nethemba 