DPP4 Inhibition in Human Kidney Proximal Tubular Cells - Renoprotection in Diabetic Nephropathy?

Abstract

Novel diabetic drugs that target the incretin system e.g dipeptidyl peptidase 4 (DPP4) inhibitors have pleiotropic effects other than inhibiting the cleavage of glucagon like peptide 1 (GLP-1). As DPP4 is located at the brush border of the kidney proximal tubular cells (PTC), we hypothesise that it is involved in the processing of luminal peptides influencing the kidney tubulointerstitium in diabetes. Using HK2 cells (human kidney proximal tubular cell line) in order to study the GLP-1 independent effects of DPP4 inhibition on the PTC cells were exposed to high glucose conditions, high mobility protein 1(HMGB1) and meprin beta. Relevant markers like DPP4, fibronectin, collagen IV, transforming growth factor beta (TGF beta), activator protein 1(AP-1) and nuclear factor-kappa B (NF-kappa B) were measured. We show that linagliptin (DPP4 inhibitor) interferes with the activation of TGF beta and downstream reduction in fibronectin but not collagen IV expression. Linagliptin reduced HMGB1 but not high glucose induced NF-kappa B binding. Linagliptin also reduced high glucose induced AP-1 binding. Meprin beta peptides induce AP-1 binding and this was unchanged with linagliptin. Our data provides new insight into the GLP-1 independent role of DPP4 inhibition in kidney PTC exposed to stimuli relevant in diabetic renal complications. Identifying the functionally relevant renal substrates of DPP4 will help us understand and anticipate long term effects on the kidney in patients with diabetes.