P0110DPP4- INHIBITOR LINAGLIPTIN ACCELERATES RESOLUTION OF CRESCENT FORMATION IN A RAT MODEL OF ANTI-GBM GLOMERULONEPHRITIS

Abstract

Abstract Background and Aims Crescent formation is a severe glomerular damage in the pathogenesis of different kidney diseases. However the exact pathomechanism of crescent formation is unclear up to now. In human kidney biopsies we observed high dipeptidyl peptidase 4 (DPP4) expression in early crescent formation. Therefore, we investigated the potential involvement of DPP4 in the pathogenesis of crescentic anti-GBM nephritis in a rat model using a DPP4- inhibitor independent of his present use in the treatment of type 2 diabetes. Method Anti-GBM nephritis was induced in Wistar Kyoto rats for investigation of short and long term effects of the DPP4- inhibitor linagliptin treatment (3 mg/kg bw). In the short term experiment (endpoint 2 weeks) linagliptin treatment was started either with model induction or one week later. In the long term experiment (endpoint 8 weeks) linagliptin treatment was started either on day 0 or on week 4. In both experiments we included an untreated healthy and anti-GBM nephritic group. All groups consisted of 11 animals. Kidney function was monitored on weeks 1, 2, 3, 5 and 8. Kidney tissue was used to determine DPP4 expression and activity, morphologic changes and mRNA expression. Results Similarly to our observation in human kidney biopsies the in situ DPP4 activity and DPP4 expression were both increased in nephritic glomeruli especially within the crescents. Linagliptin could almost completely inhibit all renal DPP4 activity without any effect on DPP4 expression. Short-term treatment had no significant effect on crescent formation. However, long-term preventive treatment resulted in reduced number of crescents (51±3% vs 65±3%), glomerulosclerosis (score 1.2±0.07 vs 1.6±0.1), tubulointerstitial 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. Therapeutic intervention with linagliptin resulted in weaker amelioration of renal disease at week 8, but also significantly reduced renal fibrosis (score 1.4±0.13 vs. 1.9±0.14) and crescent formation (52±4% vs. 65±3%) compared with vehicle. About 20% of all glomeruli showed Pax8+ parietal epithelial cells (PECs) on the tuft in short term treatment, being significantly reduced by therapeutic linagliptin treatment on day 14. In the long term experiment the number of Pax8+ PECs on glomerular tuft was reduced by more than 50% in both treatment groups and confirmed by quantitative mRNA analysis using isolated glomeruli. Despite the number of Pax8-positive cells on glomerular tuft was reduced by linagliptin therapy, a subpopulation of PECs positive for the transcription factor SOX9 was significantly increased on glomerular tuft compared to healthy and non-treated rats on day 14. Conclusion DPP4- inhibition with linagliptin reduced Pax8+ cells on glomerular tuft, indicating accelerated resolution of formed crescents and improvement in renal injury. This DDP4 effect might be mediated by differential regulation of a subpopulation of PECs expressing the transcription factor SOX9.