Abstract 10434: Cardio- and Reno-Protective Effects of Dipeptidyl Peptidase III

Dipeptidyl peptidase (DPP) III, like DPP IV, is an enzyme that cleaves two amino acids from the N-terminus of specific peptides. The physiological and pathological functions of DPP III have not been understood well. Because DPP III was reported to catalyze angiotensin II (Ang II), we investigated the catalytic property of DPP III for Ang II in vitro and the effect of DPP III on blood pressure in vivo. DPP III digested Ang II with Km = 3.7х10 mol/L and Vmax = 3.3х10 mol/L/sec. When DPP III was intravenously administered in the control normotensive mice, blood pressure and heart rate did not change. In contrast, DPP III significantly reduced blood pressure to the normal level in Ang II-infused hypertensive mice without alteration in heart rate. In the Ang II-infused mice, increased plasma concentration of Ang II was actually decreased by treatment with DPP III. In addition, DPP III did not reduce blood pressure in norepinephrine-infused hypertensive mice, indicating that the blood pressure-lowering effect of DPP III is specific to Ang II-induced hypertension. Repeated administration of DPP III for 4 weeks prevented the Ang II-induced cardiac hypertrophy and fibrosis as well as proteinuria and renal damage. Next, we used highly diabetic db/db mice. These mice had normal blood pressure, but showed abundant excretion of albumin in the urine due to renal dysfunction. Treatment with DPP III for 8 weeks in these mice remarkably attenuated proteinuria without alteration in blood pressure, heart rate, and plasma glucose concentration. In the immunofluorescence microscopy, abnormal accumulation of podocin and disorganized thickness of slit diaphragm observed in the db/db mouse kidney were improved by DPP III treatment. In the electron microscopy, the disturbance of the foot process of podocytes in the glomeruli of db/db mice was rescued by administration of DPP III. The peptides that were increased in the serum of db/db mice and were cleaved by DPP III were considered to cause the adverse phenomena in the kidney. Taken together, these results suggest that DPP III has both cardio- and reno-protective effects in different pathological models.