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Cardio- and reno-protective effects of dipeptidyl peptidase III in diabetic mice.

ABSTRACT: Diabetes mellitus (DM) causes injury to tissues and organs, including to the heart and kidney, resulting in increased morbidity and mortality. Thus, novel potential therapeutics are continuously required to minimize DM-related organ damage. We have previously shown that dipeptidyl peptidase III (DPPIII) has beneficial roles in a hypertensive mouse model, but it is unknown whether DPPIII has any effects on DM. In this study, we found that intravenous administration of recombinant DPPIII in diabetic db/db mice for 8 weeks suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. This treatment inhibited inflammatory cell infiltration and fibrosis in the heart and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was, at least in part, mediated by the cleavage of a cytotoxic peptide, named Peptide 2, which was increased in db/db mice compared with normal mice. This peptide consisted of nine amino acids, was a digested fragment of complement component 3 (C3), and had an anaphylatoxin-like effect determined by the Miles assay and chemoattractant analysis. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in a DM animal model through cleavage of a peptide that is a part of C3.

SUBMITTER: Komeno M

PROVIDER: S-EPMC8167299 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Exploration of peptides that are increased in the plasma of diabetic mice and are the substrate of dipeptidyl peptidase III

Project description:Diabetes mellitus (DM) causes the change in the components of the plasma, which may induce tissue and organ injuries, including the heart and kidney. In the diabetic model db/db mice, intravenous injection of purified dipeptidyl peptidase III (DPPIII) attenuated the heart and kidney damages provoked by DM without alteration in blood glucose level. This led us to hypothesize that there might be peptide(s) that are involved in the progression of the DM-mediated damages and are cleaved by DPPIII. To explore the peptides, the whole peptidomics analysis was conducted using tandem mass spectrometry, in which peptides derived from the plasma of PBS-infused C57BL/6 mice, PBS-infused db/db mice, and DPPIII-treated db/db mice were compared. All of the lists of the peptides in the three mouse groups were shown in the raw data formatted and excel files.

2022-02-17 | PXD025440 | Pride

Dipeptidyl peptidase-4 plays a pathogenic role in BSA-induced kidney injury in diabetic mice.

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Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects.

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The Role of Dipeptidyl Peptidase - 4 Inhibitors in Diabetic Kidney Disease.

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Dipeptidyl peptidase-IV is associated with decreased glioma growth

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2011-12-31 | E-MTAB-583 | biostudies-arrayexpress

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| S-EPMC8878202 | biostudies-literature

Protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitor against increased ? cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes.

Project description:Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces ? cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged ? cell-specific glucokinase haploinsufficient (Gck(+/-)) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed ? cell apoptosis. In Gck(+/-) but not wild-type mice, SL significantly decreased the ? cell mass and ? cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck(+/-) mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against ? cell apoptosis, restored the ? cell mass, and normalized islet morphology in Gck(+/-) mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced ? cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated ? cell apoptosis in diabetic Gck(+/-) mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.

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Identification of an Additional Metal-Binding Site in Human Dipeptidyl Peptidase III.

Project description:Dipeptidyl peptidase III (DPP III, EC 3.4.14.4) is a monozinc metalloexopeptidase that hydrolyzes dipeptides from the N-terminus of peptides consisting of three or more amino acids. Recently, DPP III has attracted great interest from scientists, and numerous studies have been conducted showing that it is involved in the regulation of various physiological processes. Since it is the only metalloenzyme among the dipeptidyl peptidases, we considered it important to study the process of binding and exchange of physiologically relevant metal dications in DPP III. Using fluorimetry, we measured the Kd values for the binding of Zn2+, Cu2+, and Co2+ to the catalytic site, and using isothermal titration calorimetry (ITC), we measured the Kd values for the binding of these metals to an additional binding site. The structure of the catalytic metal's binding site is known from previous studies, and in this work, the affinities for this site were calculated for Zn2+, Cu2+, Co2+, and Mn2+ using the QM approach. The structures of the additional binding sites for the Zn2+ and Cu2+ were also identified, and MD simulations showed that two Cu2+ ions bound to the catalytic and inhibitory sites exchanged less frequently than the Zn2+ ions bound to these sites.

| S-EPMC10454320 | biostudies-literature

Reno-protective effects of renin-angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis.

Project description:Aims/hypothesisThis meta-analysis aimed to compare the renal outcomes between ACE inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and other antihypertensive drugs or placebo in type 2 diabetes.MethodsPublications were identified from Medline and Embase up to July 2011. Only randomised controlled trials comparing ACEI/ARB monotherapy with other active drugs or placebo were eligible. The outcome of end-stage renal disease, doubling of serum creatinine, microvascular complications, microalbuminuria, macroalbuminuria and albuminuria regression were extracted. Risk ratios were pooled using a random-effects model if heterogeneity was present; a fixed-effects model was used in the absence of heterogeneity.ResultsOf 673 studies identified, 28 were eligible (n = 13-4,912). In direct meta-analysis, ACEI/ARB had significantly lower risk of serum creatinine doubling (pooled RR = 0.66 [95% CI 0.52, 0.83]), macroalbuminuria (pooled RR = 0.70 [95% CI 0.50, 1.00]) and albuminuria regression (pooled RR 1.16 [95% CI 1.00, 1.39]) than other antihypertensive drugs, mainly calcium channel blockers (CCBs). Although the risks of end-stage renal disease and microalbuminuria were lower in the ACEI/ARB group (pooled RR 0.82 [95% CI 0.64, 1.05] and 0.84 [95% CI 0.61, 1.15], respectively), the differences were not statistically significant. The ACEI/ARB benefit over placebo was significant for all outcomes except microalbuminuria. A network meta-analysis detected significant treatment effects across all outcomes for both active drugs and placebo comparisons.Conclusions/interpretationOur review suggests a consistent reno-protective effect of ACEI/ARB over other antihypertensive drugs, mainly CCBs, and placebo in type 2 diabetes. The lack of any differences in BP decrease between ACEI/ARB and active comparators suggest this benefit is not due simply to the antihypertensive effect.

| S-EPMC3268972 | biostudies-literature

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