DPP-4 inhibition enhanced renal tubular and myocardial GLP-1 receptor expression decreased in CKD with myocardial infarction

Abstract

Background: Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and is a significant risk factor for increased morbidity and mortality. In contrast, GLP-1 receptor (GLP-1R) activation has been shown to confer both renal and cardiovascular protection, though its relationship with CKD and CKD with myocardial ischemia/reperfusion (MI/R) remains poorly understood. Here, we investigated changes in renal and myocardial GLP-1R expression in the CKD rat model with MI/R. Methods: Male Sprague Dawley rats with 5/6 nephrectomy were used as a rat model of CKD and CKD with MI/R. For myocardial ischemia, the left coronary artery was ligated and released for 30 min 1 week after 5/6 nephrectomy. Dipeptidyl-peptidase 4 (DPP-4) inhibitors were administered orally with linagliptin once daily for 8 weeks. Renal cortical and myocardial GLP-1R expression were measured via immunohistochemistry and western blot analysis. Results: DPP-4 activity was increased in CKD. Western blot density of GLP-1R in renal cortex extracts revealed increased abundance 2 weeks after 5/6 nephrectomy, followed by a decrease at 8 weeks. In contrast, CKD and CKD with MI/R rats showed decreases in renal and cardiac expression of GLP-1R; these effects were attenuated in rats treated with linagliptin. Conclusions: In CKD with MI/R, linagliptin attenuated renal injury and increased renal and myocardial GLP-1R expression. These data suggest that activation of renal and myocardial GLP-1R expression may provide both cardio- and renoprotective effects.