Dipeptidyl peptidase-4 inhibitor linagliptin reduces urinary albumin excretion through the protection of glomerular endothelial function

Background: In most developed countries, diabetic kidney disease is the most common cause of chronic kidney disease, leading to end-stage renal disease, and it is also associated with cardiovascular diseases, including heart failure, and a higher risk of other microvascular complications. A recent clinical trial indicated that the dipeptidyl peptidase-4 inhibitor linagliptin prevents the occurrence and progression of albuminuria in patients with type 2 diabetes. Thus, this study aimed to elucidate the molecular mechanism underlying the inhibitory effect of linagliptin on albuminuria in diabetic kidney disease. Methods: Control C57BL/6 mice and diabetic Ins2 +/Akita mice were orally administered linagliptin (5 mg/kg/day) every day for 8 weeks. Results: Compared to control mice, Ins2 +/Akita mice had markedly elevated blood glucose and HbA1c levels, but there were no significant changes after linagliptin treatment. Furthermore, albuminuria and urinary 8-OHdG levels were significantly increased and glomerular mesangial area was significantly expanded in Ins2 +/Akita mice compared to those in control mice; these changes were ameliorated by linagliptin treatment, which also improved the degradation of glomerular endothelial glycocalyx and enhancement of glomerular permeability of macromolecules. The activity of AMP-activated protein kinase and the expression of guanosine 5'-triphosphate cyclohydrolase I in human glomerular endothelial cells were significantly lower in high glucose conditions and were improved by linagliptin or GLP-1 administration. Discussion: These results together suggest that linagliptin reduced albuminuria in a blood glucose-independent manner via the reduction of oxidative stress and maintenance of the glycocalyx in endothelial cells. Thus, earlier treatment with linagliptin may slow the progression of diabetic kidney disease.

Kondo M, et al