Analyses for molecular mechanisms of dipeptidyl peptidase III-targeted peptide that deteriorates diabetic kidney disease

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06854
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Shimizu Akio 滋賀医科大学, 医学部, 助教 (30769279)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 糖尿病性腎臓病 / 2型糖尿病 / ペプチド / ジペプチジルペプチダーゼIII / DPPIII / 血管障害 / C3補体

Outline of Final Research Achievements

Dipeptidyl peptidase III (DPPIII) treatment in diabetic db/db mice suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. The 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 mediated by the cleavage of a cytotoxic peptide, which was increased in db/db mice compared with normal mice. The peptide had an anaphylatoxin-like effect. 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 the DM animal model through cleavage of the peptide that is a part of C3.

Free Research Field

生化学　循環器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、DPPIIIが2型糖尿病モデルマウスであるdb/dbマウスにおいて、糖尿病性腎症の増悪は、DPP III投与によって、血糖値、血圧、心機能に変動なく有意に抑制されることを見出した。つまり、DPP IIIは血糖や血圧の調節とは独立して糸球体保護作用を発揮し、糖尿病性腎症を抑制する全く新しい効果を有していることが判明した。糖尿病の治療は発達しているものの、糖尿病性腎症は増加傾向にある。このことは、糖尿病性腎症の克服には単純に血糖値を正常化するだけでは不十分であり、新たな治療法の開発、創薬が必要であることを意味している。