Dipeptidyl peptidase 4 (DPP4) 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 DPP4 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 DPP4 in the pathogenesis of nephritis induced by anti-glomerular basement membrane (GBM) antibody in rats.
Linagliptin and vehicle were used to treat anti-GBM nephritis in a 2 and 8-week regimen: i.e. either preventive or therapeutic (treatment started 7 days or 4 weeks after model induction). Kidney function, morphologic changes, inflammation and fibrosis were monitored.
In the long-term experiment linagliptin preventive treatment in anti-GBM nephritic rats significantly reduced the number of crescents, glomerulosclerosis, tubular injury, renal fibrosis compared with 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 compared with preventive intervention.
DPP4 inhibition with linagliptin ameliorates renal injury in a rat model of anti-GBM indicating that linagliptin is a secure therapy not only in diabetes but can also improve resolution of glomerular injury and healing in non-diabetic renal disease.
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