Novel repair mechanisms in a renal ischaemia/reperfusion model: Subsequent saxagliptin treatment modulates the pro-angiogenic GLP-1/cAMP/VEGF, ANP/eNOS/NO, SDF-1α/CXCR4, and Kim-1/STAT3/HIF-1α/VEGF/eNOS pathways.

Abstract

The reno-protective effects of antidiabetic dipeptidyl peptidase (DPP)-4 inhibitors have been studied regarding their antioxidant and anti-inflammatory properties. However, the potential ability of saxagliptin to ameliorate renal injury by enhancing neovascularization has not been elucidated. To address this issue, saxagliptin (10 and 30\u202fmg/kg) was administered to Wistar rats after the induction of renal ischaemia/reperfusion (I/R). Our results showed that saxagliptin operated through different axes to ameliorate I/R injury. By inhibiting DPP-4, saxagliptin maintained stromal cell-derived factor-1α expression and upregulated its chemokine receptor CXCR4 to trigger vasculogenesis through the enhanced migration of endothelial progenitor cells (EPCs). Additionally, this compound rescued the levels of glucagon-like peptide-1 and its downstream mediator cAMP to increase vascular endothelial growth factor (VEGF) and CXCR4 levels. Moreover, saxagliptin stimulated atrial natriuretic peptide/endothelial nitric oxide synthase to increase nitric oxide levels and provoke angiogenesis and renal vasodilation. In addition to inhibiting DPP-4, saxagliptin increased the renal kidney injury molecule-1/pY705-STAT3/hypoxia-inducible factor-1α/VEGF pathway to enhance angiogenesis. Similar to other gliptins, saxagliptin exerted its anti-inflammatory and antioxidant effects by suppressing the renal contents of p (S536)-nuclear factor-κB p65, tumour necrosis factor-α, monocyte chemoattractant protein-1, myeloperoxidase, and malondialdehyde while boosting the glutathione content. These events improved the histological structure and function of the kidney, as evidenced by decreased serum creatinine, blood urea nitrogen, and cystatin C and increased serum albumin. Accordingly, in addition to its anti-inflammatory and antioxidant activities, saxagliptin dose-dependently ameliorated I/R-induced renal damage by enhancing neovascularization through improved tissue perfusion and homing of bone marrow-derived EPCs to mediate repair processes.