Rapid improvement of renal microcirculatory homeostasis by liraglutide following diabetes induction

Abstract Aims Renal microvascular dysfunction is a central driver of diabetic kidney disease, yet the potential for rapid therapeutic reversal remains obscure. We investigated the effect of short‐term liraglutide on early changes in the renal microcirculation post‐induction of diabetes. Materials and Methods Type 2 diabetes mellitus (T2DM) was induced in BALB/c mice via high‐fat diet and streptozotocin. Following induction, mice received insulin or liraglutide treatments for 1 or 2 weeks. Renal microhemodynamics was analysed using laser Doppler flowmetry and wavelet analysis. Histopathological evaluations via Masson trichrome and haematoxylin–eosin staining assessed fibrosis and microvascular integrity. Primary renal microvascular endothelial cells (RMECs) were isolated to evaluate angiogenic and migratory behaviours. Metabolomics analyses were performed to link metabolic changes with microcirculatory alterations. Results T2DM induced significant impairments in renal microcirculation, characterised by dysregulated microhemodynamics, disturbed oxygen saturation, altered haemoglobin distribution and compromised blood perfusion. These functional defects were accompanied by elevated creatinine, reduced cystatin C and impaired angiogenic and migratory capacity of RMECs under glucotoxicity. Both insulin and liraglutide treatments ameliorated renal microcirculatory oxygen profiles and improved renal function biomarkers. Histological data revealed decreased fibrosis and enhanced microvascular architecture post‐treatment. Metabolomic profiling revealed that liraglutide preferentially restored depleted amino acid levels associated with microvascular function, a change associated with the normalisation of metabolic profiles potentially involving peptide transport pathways. Conclusions Our findings demonstrate that short‐term liraglutide restores renal microcirculatory homeostasis in the post‐induction phase, mitigating microvascular dysfunction and preserving kidney structure, highlighting the potential therapeutic value in preventing the progression of diabetic renal injury.