The DPP4 inhibitor linagliptin ameliorated renal injury and accelerated resolution in a rat model of crescentic nephritis

Background and PurposeDipeptidyl peptidase 4 (DPP‐4) inhibitors are a class of oral glucose‐lowering drugs used in the treatment of type 2 diabetes. In a pilot study using human kidney biopsies, we observed high DPP‐4 expression in early crescent formation. This glomerular lesion occurs in different kidney diseases and is a hallmark in the pathogenesis of renal dysfunction. Therefore, we investigated the potential involvement of DPP‐4 in the pathogenesis of nephritis induced by anti‐glomerular basement membrane (GBM) antibody in rats.Experimental ApproachLinagliptin and vehicle were used to treat anti‐GBM nephritis in a 2‐ and 8‐week regimen, that is either preventive or therapeutic (treatment started 7 days or 4 weeks after disease induction). Kidney function, morphologic changes, inflammation and fibrosis were monitored.Key ResultsIn the long‐term experiment, linagliptin preventive treatment in anti‐GBM nephritic rats significantly reduced the number of crescents, glomerulosclerosis, tubular injury and renal fibrosis, compared with those in untreated nephritic rats. Both linagliptin regimes significantly lowered the number of Pax8+ cells on the glomerular tuft in anti‐GBM nephritis, indicating accelerated resolution of the cellular crescents. The linagliptin treatment did not change the number but the podocyte stress in both therapeutic groups. Therapeutic intervention with linagliptin resulted in weaker amelioration of renal disease on Week 8 than did preventive intervention.Conclusion and ImplicationsDPP‐4 inhibition with linagliptin ameliorates renal injury in a rat model of anti‐GBM, indicating that linagliptin not only is a secure therapy in diabetes but also can improve resolution of glomerular injury and healing in non‐diabetic renal disease.