Abstract
BackgroundChronic 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.MethodsMale 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.ResultsDPP-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.ConclusionsIn 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.
Highlights
Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and is a significant risk factor for increased morbidity and mortality
Joo et al reported no changes in Dipeptidyl-peptidase 4 (DPP-4) activity at 8 weeks of CKD [26], we found the DPP-4 inhibitory activity of linagliptin to be much higher in advanced CKD
We found GLP-1 receptor (GLP-1R) expression was increased after DPP-4 inhibition, and it is thought to be associated with ligand-receptor interaction
Summary
Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and is a significant risk factor for increased morbidity and mortality. The presence of CKD, whether manifested as albuminuria or reduced glomerular filtration rate, has been identified as an independent cardiovascular risk factor and is associated with higher mortality [2]. Cardiovascular disease is the most common cause of death in CKD [4], with a prevalence 10 times higher than that of the general population [5]. Numerous interventions have been developed that target known cardiovascular risk factors, with a goal of reducing mortality in CKD patients. Targeting of left ventricular problems associated with coronary artery disease [6], as well as prevention of vascular calcification and coronary atherosclerosis, have proven effective for reducing the risk of cardiovascular events in CKD patients [7, 8]
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