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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.

SUBMITTER: Kim SJ

PROVIDER: S-EPMC6397488 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Kim Seung Jung SJ Kwon Soon Kil SK Kim Hye-Young HY Kim Sun Moon SM Bae Jang-Whan JW Choi Joong-Kook JK

BMC nephrology 20190301 1

<h4>Background</h4>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 ...[more]

PMID: 30823876

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Project description:BackgroundISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) reported an initial invasive treatment strategy did not reduce the risk of death or nonfatal myocardial infarction (MI) compared with a conservative treatment strategy in patients with advanced chronic kidney disease, stable coronary disease, and moderate or severe myocardial ischemia. The cumulative frequency of different MI type after randomization and subsequent prognosis have not been reported.MethodsMI classification was based on the Third Universal Definition for MI. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary MI definition used cTn (cardiac troponin); both definitions included elevated biomarker-only events with higher thresholds than nonprocedural MIs. The cumulative frequency of MI type according to treatment strategy was determined. The association of MI with subsequent all-cause death and new dialysis initiation was assessed by treating MI as a time-dependent covariate.ResultsThe 3-year incidence of type 1 or 2 MI with the primary MI definition was 11.2% in invasive treatment strategy and 13.6% in conservative treatment strategy (hazard ratio [HR], 0.66 [95% CI, 0.42-1.02]). Procedural MIs were more frequent in invasive treatment strategy and accounted for 9.8% and 28.3% of all MIs with the primary and secondary MI definitions, respectively. Patients had an increased risk of all-cause death after type 1 MI (adjusted HR, 4.35 [95% CI, 2.73-6.93]) and after procedural MI with the primary (adjusted HR, 2.75 [95% CI, 0.99-7.60]) and secondary MI definitions (adjusted HR, 2.91 [95% CI, 1.73-4.88]). Dialysis initiation was increased after a type 1 MI (HR, 6.45 [95% CI, 2.59-16.08]) compared with patients without an MI.ConclusionsIn ISCHEMIA-CKD, the invasive treatment strategy had higher rates of procedural MIs, particularly with the secondary MI definition, and lower rates of type 1 and 2 MIs. Procedural MIs, type 1 MIs, and type 2 MIs were associated with increased risk of subsequent death. Type 1 MI increased the risk of dialysis initiation.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT01985360.

Project description:Dipeptidyl peptidase-4 (DPP-4) is a proteolytic enzyme responsible for the rapid degradation of Glucagon-like peptide 1 (GLP-1) that is required for the secretion of insulin. DPP-4 also influences activation of node like receptor family, pyrin domain containing 3 (NLRP3) inflammasome under diabetic conditions. Although several polyphenols are reported for various bioactivities, they are consumed as part of the food matrix and not in isolation. Horsegram (Macrotyloma uniflorum) is a rich source of myricetin (Myr) (35 ?g/g flour), reported for its anti-hyperglycemic effect. In this investigation, we aimed to study the effect of Myr, singly, and in the presence of co-nutrient horsegram protein (HP) on DPP-4 activity and its consequential impact on GLP-1, insulin, and NLRP3 inflammasome in high-fat diet and single low dose streptozotocin (STZ)-induced diabetic male Wistar rats. In diabetic control (DC), the activity of DPP-4 and its expression were higher compared to treated groups. The consequential decrease in the circulating GLP-1 levels in the DC group, but not treated groups, further indicated the effectiveness of our test molecules under diabetic conditions. Specifically, Myr decreased DPP-4 activity and its expression levels with enhanced circulating GLP-1 and insulin levels. Myr administration also resulted in a lessening of diabetes-induced NLRP3 inflammasome activation and enhanced antioxidant enzyme activities. HP also proved to be efficient in reducing elevated blood glucose levels and enhancing antioxidant enzyme activities. However, Myr, in the presence of HP as a co-nutrient, had diminished capacity to inhibit DPP-4 and, consequently, reduced potential in ameliorating diabetic conditions. Myr proved to be a potent inhibitor of DPP-4 in vitro and in vivo, resulting in enhanced circulating GLP-1 and insulin levels, thereby improving diabetic conditions. Though Myr and HP, individually ameliorate diabetic conditions, their dietary combination had reduced efficiency.

Project description:AIMS/HYPOTHESIS:Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis. METHODS:We have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRA?Null) or is expressed exclusively in the intestine (GcgRA?VilCre) or pancreas and duodenum (GcgRA?PDX1Cre). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists. RESULTS:Administration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRA?Null mice and control littermates and in GcgRA?VilCre and GcgRA?PDX1Cre mice. The potent GLP-1 receptor antagonist, exendin-[9-39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRA?PDX1Cre mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRA?Null or in GcgRA?VilCre mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRA?Null mice. CONCLUSIONS/INTERPRETATION:Taken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.

Dataset Information

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

Publications

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

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