Reno-Protective Effect of Liraglutide in T1DM: Modulating HIF1-α/ HIF2-α Downstream Signaling Pathways

Abstract

Diabetic kidney disease (DKD) is a leading microvascular complication of diabetes and a major cause of end-stage renal disease. Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has shown promise in preserving renal function, though its mechanism of action in type 1 diabetes mellitus (T1DM) remains unclear. Recent evidence implicates hypoxia-inducible factors (HIFs), particularly the imbalance between HIF-1α and HIF-2α, in the pathogenesis of DKD. This study aimed to investigate the reno-protective effect of Liraglutide in a streptozotocin-induced mouse model of T1DM, with a focus on modulation of HIF signaling. Mice were divided into control (C), diabetic (D), and diabetic plus Liraglutide (DL) groups. Renal function, histopathology, mRNA, and protein expression of key hypoxia, injury, and podocyte markers were assessed. Liraglutide did not normalize hyperglycemia or HbA1c but significantly reduced albuminuria, blood urea nitrogen, and proteinuria. Histologically, it attenuated glomerulosclerosis, collagen deposition, and preserved podocyte integrity. Mechanistically, Liraglutide reversed the diabetic kidney’s imbalance in HIF signaling, suppressing HIF-1α and upregulating HIF-2α, and modulated their downstream targets, including E-cadherin and erythropoietin (EPO). These findings support a glycemia-independent reno-protective role for Liraglutide in T1DM through restoration of HIF-1α/HIF-2α balance. Targeting hypoxia- driven pathways may enhance therapeutic strategies for DKD in T1DM.