Background: Diabetes mellitus (DM) is increasing and a third of patients will suffer diabetic nephropathy (DN) as a complication. Linagliptin is an oral diabetic agent used to lower blood glucose in type 2 DM. It inhibits cleavage of the endogenous incretin hormones GLP-1 and GIP, raising its levels and thus promoting insulin release and inhibiting glucagon secretion resulting in lowering of blood glucose. DPP4 also cleaves a host of additional peptides (not just GLP-1/ GIP) and interacts with other membrane proteins such as cation independent mannose 6 phosphate receptor (CIM6PR) in a non enzymatic fashion. We have previously demonstrated that linagliptin inhibits the conversion of high glucose induced latent to active transforming growth factor beta (TGFB), a key profibrotic cytokine as well as downstream smad signalling and fibronectin expression. We have also shown that CIM6PR is involved in the conversion of latent to active TGFB in HK2 cells. This study investigates whether linagliptin interrupts the co-localisation of DPP4 and CIM6PR and hence the conversion of latent to active TGFB.
Methods: HK2 cells were exposed to control (5mM) or high glucose (30mM) +/- linagliptin (30nM). Cells were then subjected to a proximity ligation assay with primary antibodies directed against DPP4 and CIM6PR.
Results: High glucose exposure increased the co-localisation of DPP4 and CIM6PR and this was reduced in the presence of linagliptin.
Conclusions: Linagliptin inhibits the conversion of high glucose induced latent to active TGFB through CIM6PR and may offer renoprotection in diabetic nephropathy.