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A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice.

ABSTRACT: Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.

SUBMITTER: Min HS

PROVIDER: S-EPMC8003165 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice.

Min Hye Sook HS Lee Ji Eun JE Ghee Jung Yeon JY Kang Young Sun YS Cha Jin Joo JJ Han Jee Young JY Han Sang Youb SY Cha Dae Ryong DR

Life (Basel, Switzerland) 20210318 3

Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg ...[more]

PMID: 33803842

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Project description:PurposeEvogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase IV (DPP-IV) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles and tolerability of evogliptin after repeated oral administration in healthy subjects.Patients and methodsA block-randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed in a total of 30 subjects. Repeated once-daily doses of 5, 10, or 20 mg evogliptin or the same doses of placebo were orally administered to ten subjects in each dosage group for 10 days. Subjects in each group were randomized to receive evogliptin or placebo with a ratio of 8:2. Pharmacokinetics of evogliptin were evaluated, with its concentrations in serial plasma and urine samples collected following the first and last administrations. DPP-IV activity and glucagon-like peptide-1, glucose, and insulin levels were quantified to evaluate evogliptin's pharmacodynamics on the first and last dosing days.ResultsAll participants completed the study without any serious or severe adverse event. The evogliptin plasma concentration reached its peak within 4-5 hours and decreased relatively slowly, with a terminal elimination half-life of 33-39 hours. Repeated administration resulted in a 1.4- to 1.5-fold accumulation. Evogliptin's systemic exposure and inhibition of plasma DPP-IV activity increased in a dose-dependent manner. Inhibition of DPP-IV activity >80% was sustained over 24 hours in all evogliptin dose groups and provided an increase in postprandial active glucagon-like peptide-1 levels by 1.5- to 2.4-fold. Postprandial glucose levels in the evogliptin-treated groups were reduced 20%-35% compared to placebo, but were not accompanied by increased insulin levels.ConclusionRepeated administration of evogliptin in healthy subjects was well tolerated and exhibited linear pharmacokinetics within the 5-20 mg dose range. A once-daily regimen of 5-20 mg evogliptin effectively inhibited DPP-IV activity.

Project description:Aims/introductionRecent data showed that dipeptidyl peptidase 4 (DPP-4) inhibitors exert a lipid-lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non-diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol-lowering action.Materials and methodsMale apolipoprotein E (ApoE)-deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of 14 C-labeled cholesterol (14 C-Chol). In additional experiments, effects of exendin-4 in mice and of anagliptin in DPP-4-deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice.ResultsThe serum total and non-high-density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE-deficient mice. The cholesterol-lowering effect was predominantly observed in the chylomicron fraction. The plasma 14 C-Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal 14 C-Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP-4 activity, and exendin-4 had no effect on the 14 C-Chol transport in ApoE-deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport-related microsomal triglyceride transfer protein, acyl-coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin.ConclusionsThese findings suggest that anagliptin might exert a cholesterol-lowering action through DPP-4-dependent and glucagon-like peptide 1-independent suppression of intestinal cholesterol transport.

Project description:Background and objectiveBrensocatib is an investigational, first-in-class, selective, and reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases (NSPs). The NSPs neutrophil elastase, cathepsin G, and proteinase 3 are believed to be central to the pathogenesis of several chronic inflammatory diseases, including bronchiectasis. In a phase II study, oral brensocatib 10 mg and 25 mg reduced sputum neutrophil elastase activity and prolonged the time to pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE). A population pharmacokinetic (PPK) model was developed to characterize brensocatib exposure, determine potential relationships between brensocatib exposure and efficacy and safety measures, and inform dose selection in clinical studies.MethodsPharmacokinetic (PK) data pooled from a phase I study of once-daily brensocatib (10, 25, and 40 mg) in healthy adults and a phase II study of once-daily brensocatib (10 mg and 25 mg) in adults with NCFBE were used to develop a PPK model and to evaluate potential covariate effects on brensocatib pharmacokinetics. PK-efficacy relationships for sputum neutrophil elastase below the level of quantification (BLQ) and reduction in pulmonary exacerbation and PK-safety relationships for adverse events of special interest (AESIs; periodontal disease, hyperkeratosis, and infections other than pulmonary infections) were evaluated based on model-predicted brensocatib exposure. A total of 1284 steady-state brensocatib concentrations from 225 individuals were included in the PPK data set; 241 patients with NCFBE from the phase II study were included in the pharmacodynamic (PD) population for the PK/PD analyses.ResultsThe PPK model that best described the observed data consisted of two distributional compartments and linear clearance. Two significant covariates were found: age on volume of distribution and renal function on apparent oral clearance. PK-efficacy analysis revealed a threshold brensocatib exposure (area under the concentration-time curve) effect for attaining sputum neutrophil elastase BLQ and a strong relationship between sputum neutrophil elastase BLQ and reduction in pulmonary exacerbations. A PK-safety evaluation showed no noticeable trends between brensocatib exposure and the incidence of AESIs. Based on the predicted likelihood of clinical outcomes for sputum neutrophil elastase BLQ and pulmonary exacerbations, brensocatib doses of 10 mg and 25 mg once daily were selected for a phase III clinical trial in patients with NCFBE (ClinicalTrials.gov identifier: NCT04594369).ConclusionsPPK results revealed that age and renal function have a moderate effect on brensocatib exposure. However, this finding does not warrant dose adjustments based on age or in those with mild or moderate renal impairment. The PK/PD evaluation demonstrated the clinically meaningful relationship between suppression of neutrophil elastase activity and reduction in exacerbations in brensocatib-treated patients with NCFBE, supporting further development of brensocatib for bronchiectasis.

Project description:Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor-associated angioedema. This case-control study tested the hypothesis that dipeptidyl peptidase IV activity and antigen are decreased in sera of patients with a history of angiotensin-converting enzyme inhibitor-associated angioedema. Fifty subjects with a history of angiotensin-converting enzyme inhibitor-associated angioedema and 176 angiotensin-converting enzyme inhibitor-exposed control subjects were ascertained. Sera were assayed for angiotensin-converting enzyme activity, aminopeptidase P activity, aminopeptidase N activity, dipeptidyl peptidase IV activity, and antigen and the ex vivo degradation half-lives of bradykinin, des-Arg(9)-bradykinin, and substance P in a subset. The prevalence of smoking was increased and of diabetes decreased in case versus control subjects. Overall, dipeptidyl peptidase IV activity (26.6+/-7.8 versus 29.6+/-7.3 nmol/mL per minute; P=0.026) and antigen (465.8+/-260.8 versus 563.1+/-208.6 ng/mL; P=0.017) were decreased in sera from individuals with angiotensin-converting enzyme inhibitor-associated angioedema compared with angiotensin-converting enzyme inhibitor-exposed control subjects without angioedema. Dipeptidyl peptidase IV activity (21.5+/-4.9 versus 29.8+/-6.7 nmol/mL per minute; P=0.001) and antigen (354.4+/-124.7 versus 559.8+/-163.2 ng/mL; P=0.003) were decreased in sera from cases collected during angiotensin-converting enzyme inhibition but not in the absence of angiotensin-converting enzyme inhibition. The degradation half-life of substance P correlated inversely with dipeptidyl peptidase IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema.

Project description:Calcineurin inhibitors are powerful immunosuppressants that revolutionized organ transplantation. However, non-immune effects of the calcineurin inhibitor, such as cyclosporine A (CsA), have significantly hindered their use. Specifically, nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage, affects up to half of all transplant patients. Calcineurin is involved in many aspects of kidney development and function; therefore, mechanisms of CsA-induced nephrotoxicity are complex and not yet fully understood. MicroRNAs are short non-coding RNAs that regulate protein-coding RNA expression through post-translational repression of target messenger RNAs. MicroRNA dysregulation is known to be involved in kidney diseases including fibrosis. In this study, we compared the renal microRNA expression profiles between mice that received CsA (20 mg/kg) or vehicle daily for six weeks. The results demonstrate that CsA induces significant changes in renal microRNA expression profile. We used combined criteria of False Discovery Rate (≤0.1), fold change (≥2) and median signal strength (≥50) and identified 76 differencially expressed microRNAs. This approach identified microRNAs previously linked to renal fibrosis that includes let-7d, miR-21, miR-29, miR-30, miR-130, miR-192, and miR-200 as well as microRNAs that have not been reported to be related to nephrotoxicity or immunosuppression. Pathway analysis of microRNA/mRNA changes highlights the Wnt, TGF-β, mTOR, and VEGF pathways. The mRNA expression profiles were compared in the same samples. The change of mRNA and microRNA profiles showed close correlations. To validate that the observed microRNA and mRNA expression level changes in mice kidney tissue were directly related to CsA treatment, the expression change induced by CsA treatment of three microRNAs (miR-21, miR-186, and miR-709) and three mRNAs (BMPR1a, SMURF1 and SMAD7) were compared in HEK293 cell line. A similar trend of expression level change was induced by CsA treatment in all selected microRNAs and mRNAs in the in vitro cell model. These data provide a roadmap for future work to study the role of the known and novel candidate microRNAs in the mechanism of nephrotoxicity and their further therapeutic potential.

Dataset Information

A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice.

Publications

A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice.

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