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

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 (DPP...

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Bibliographic Details
Published in:The Journal of biological chemistry 2021-01, Vol.296, p.100761-100761, Article 100761
Main Authors: Komeno, Masahiro, Pang, Xiaoling, Shimizu, Akio, Molla, Md Rasel, Yasuda-Yamahara, Mako, Kume, Shinji, Rahman, Nor Idayu A., Soh, Joanne Ern Chi, Nguyen, Le Kim Chi, Ahmat Amin, Mohammad Khusni B., Kokami, Nao, Sato, Akira, Asano, Yoshihiro, Maegawa, Hiroshi, Ogita, Hisakazu
Format: Article
Language:English
Subjects:
Animals
complement
Diabetes Mellitus - metabolism
Diabetes Mellitus - physiopathology
Diabetic Cardiomyopathies - drug therapy
Diabetic Cardiomyopathies - metabolism
Diabetic Cardiomyopathies - physiopathology
Diabetic Nephropathies - drug therapy
Diabetic Nephropathies - metabolism
Diabetic Nephropathies - physiopathology
diabetic nephropathy
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - therapeutic use
Enzyme Therapy
Heart - drug effects
Heart - physiopathology
heart failure
Human Umbilical Vein Endothelial Cells
Humans
Kidney - drug effects
Kidney - metabolism
Kidney - physiopathology
Male
Mice
Mice, Inbred C57BL
peptidase
peptides
permeability
Protective Agents - metabolism
Protective Agents - therapeutic use
Recombinant Proteins - metabolism
Recombinant Proteins - therapeutic use
rho
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1016/j.jbc.2021.100761