Linagliptin reduced proteinuria and renal injury in a rat model of crescentic nephritis

Background:

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a class of oral glucose lowering drugs, 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 various kidney diseases and is a pathogenic hallmark of renal dysfunction. Therefore, we investigated the potential involvement of DPP-4 in the pathogenesis of nephritis induced by anti-GBM in Wistar rats. Materials, methods: Linagliptin (3 mg/kg/bw, n = 11) or vehicle (n = 11) were used to treat anti-GBM nephritis in 8-week regimens: preventive or therapeutic (treatment started 4 weeks after model induction). Kidney function, morphologic changes, inflammation, fibrosis were monitored.

Results:

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), proteinuria (265 ± 29 vs. 363 ± 22 mg/24h) compared with untreated nephritic rats. Furthermore, the preventive linagliptin regimen significantly reduced the number of Pax8+ cells on glomerular tuft by 17 ± 5% at day 14(p < 0.05), 60 ± 5% at week 8(p < 0.001), indicating accelerated resolution of the cellular crescents. Therapeutic intervention with linagliptin resulted in weaker, but still significant amelioration of renal disease at week 8. Proteinuria was also reduced, but this result did not reach significance.

Conclusion:

DPP-4 inhibition with linagliptin ameliorates renal injury in a severe rat model with anti-GBM induced nephritis as shown by reduced crescents, proteinuria and fibrosis.Linagliptin represents a therapeutic option for diabetic patients with glomerular damage.