Abstract: SA-PO315

Mechanisms of GLP-1 Receptor Independent Renoprotective and Anti-Fibrotic Effects of DPP-4 Inhibitor Linagliptin in GLP-1 Receptor Knockout Mice with 5/6 Nephrectomy

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Hocher, Berthold, University of Potsdam, Potsdam, Germany
  • Hasan, Ahmed A., University of Potsdam, Potsdam, Germany
  • von Websky, Karoline, University of Potsdam, Potsdam, Germany
  • Reichetzeder, Christoph, University of Potsdam, Potsdam, Germany
  • Tsuprykov, Oleg, University of Potsdam, Potsdam, Germany
  • Guo, Jingli, Charité-Universitätsmedizin, Berlin, Germany
  • Delic, Denis, Boehringer Ingelheim, Biberach, Germany
  • Klein, Thomas, Boehringer Ingelheim, Biberach, Germany
Background

Dipeptidyl peptidase (DPP)-4 inhibitors were reported to have beneficial effects in experimental chronic kidney disease models. The underlying mechanisms are not clearly understood. Many studies suggested that these renoprotective effects are mediated via the glucagon like peptide-1 (GLP-1)/GLP-1 receptor pathway. To challenge this hypothesis we investigated the renal effects of the DPP-4 inhibitor linagliptin (LIN) in GLP-1r-/- mice with 5/6 nephrectomy (5/6 Nx)

Methods

The mice were allocated to the following groups: sham + wild-type + placebo (PBO); 5/6 Nx + wild-type + PBO; 5/6 Nx + wild-type + LIN; sham + GLP-1r-/- + PBO; 5/6 Nx + GLP-1r-/- + PBO and 5/6 Nx + GLP-1r-/- + LIN and the treatment period was 12 weeks

Results

5/6 Nx led to the development of renal interstitial fibrosis and glomerulosclerosis, increased plasma cystatin C levels and suppressed renal gelatinase/collagenase activity and these effects were counteracted by LIN treatment. In addition, proteins were separated from kidney tissues and subjected to LC-MALDI mass spectrometry. LIN treatment significantly up-regulated 4 peptides derived from collagen Iα1, thymosin β4, α-enolase and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and significantly down-regulated one peptide derived from Yb-1 (Nuclease-sensitive element-binding protein 1)

Conclusion

HNRNPA1 phosphorylation plays a major role in the downstream nuclear signaling of atrial natriuretic peptide (ANP) through cGMP and cGMP-dependent protein kinase. In the kidney, a disturbance of ANP-mediated cGMP synthesis is known to be a trigger of fibrosis. Also, Yb-1, α-enolase and thymosin β4 were reported to be involved in renal fibrosis through controlling TGFβ-1, PAI-1, and extracellular matrix degradation. In conclusion, the beneficial renal effects of LIN in mice with 5/6 nephrectomy cannot solely be attributed to the GLP-1/GLP-1 receptor pathway, highlighting the importance of other novel signaling pathways influenced by DPP-4 inhibition such as collagen I homeostasis, the ANP/cGMP/HNRNPA1 pathway, Yb-1, α-enolase and thymosin β4

Funding

  • Commercial Support