Linagliptin Reduced Renal Injury and Proteinuria in a Rat Model of Crescentic Nephritis

Dipeptidyl peptidase 4 (DPP-4) inhibitors are used in the treatment of type 2 diabetes. In 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. Thus, we investigated the potential involvement of DPP-4 in the pathogenesis of anti-GBM (glomerular basement membrane antibody) induced nephritis in Wistar rats. Linagliptin (3 mg/kg, n=11) and vehicle (n=11) were used to treat anti-GBM nephritis in an 8 weeks preventional and therapeutical (treatment started 4 weeks after model induction) regimen. Kidney function, morphologic changes, inflammation and fibrosis was monitored. Disease prevention with linagliptin in anti-GBM nephritic rats significantly (p<0.01) reduced the number of crescents (51±3% vs. 65±3%), glomerulosclerosis (score 1.2±0.07 vs. 1.6±0.1), tubule-interstitial injury (score 1.2±0.1 vs. 1.8±0.2), renal fibrosis (score 1.3±0.13 vs. 1.9±0.14) and proteinuria (265±29 vs. 363±22 mg/24h) compared to untreated nephritic rats. Also, preventional linagliptin therapy significantly reduced the number of Pax8+ cells on the glomerular tuft by 17±5% on day 14 (p<0.05) and 60±5% on week 8 (p<0.001), indicating accelerated resolution of the cellular crescents. Disease intervention with linagliptin resulted in weaker amelioration of renal disease on week 8 but also significantly (p<0.05) reduced renal fibrosis (score 1.4±0.13 vs. 1.9±0.14), crescent formation (52±4% vs. 65±3%) and Pax8-positive cells on glomerular tuft (65±5.2% reduction) compared to vehicle. Proteinuria was also reduced but did not reach significance. In conclusion, DPP-4 inhibition by linagliptin ameliorates renal injury in a severe rat model with anti-GBM induced nephritis as shown by reduced crescents, proteinuria and fibrosis, and resolution of crescents. Therapeutic intervention with linagliptin showed weaker effects compared to a preventional mode. Disclosure A. Mayer: Research Support; Spouse/Partner; Boehringer Ingelheim Pharmaceuticals, Inc.. K.U. Amann: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. C. Daniel: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..