Saxagliptin reduces renal tubulointerstitial inflammation, hypertrophy and fibrosis in diabetes

AimIn addition to lowering blood glucose in patients with type 2 diabetes mellitus, dipeptidyl peptidase 4 (DPP4) inhibitors have been shown to be antifibrotic and anti-inflammatory. We have previously shown that DPP4 inhibition in human kidney proximal tubular cells exposed to high glucose reduced fibrotic and inflammatory markers. Hence, we wanted to demonstrate renoprotection in an in vivo model. MethodsWe used a type 1 diabetic animal model to explore the renoprotective potential of saxagliptin independent of glucose lowering. We induced diabetes in enos -/- mice using streptozotocin and matched glucose levels using insulin. Diabetic mice were treated with saxagliptin and outcomes compared with untreated diabetic mice. ResultsWe provide novel data that saxagliptin limits renal hypertrophy, transforming growth factor beta-related fibrosis and NF-Bp65-mediated macrophage infiltration. Overall, there was a reduction in histological markers of tubulointerstitial fibrosis. There was no reduction in albuminuria or glomerulosclerosis. ConclusionOur findings highlight the potential of DPP4 inhibition as additional therapy in addressing the multiple pathways to achieve renoprotection in diabetic nephropathy. Summary at a Glance The authors found that treatment of diabetic enos-/- mice with the DPP4 inhibitor Saxagliptin led to inhibition of tubulointerstitial fibrosis, independent of its glucose lowering effects, thus highlighting the potential of DDP4 inhibitors as adjunct therapy in diabetic nephropathy.