DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury

• Published in: Laboratory investigation 2016-05, Vol.96 (5), p.547-560
• Main Authors: Eun Lee, Jee, Kim, Jung Eun, Lee, Mi Hwa, Song, Hye Kyoung, Ghee, Jung Yeon, Kang, Young Sun, Min, Hye Sook, Kim, Hyun Wook, Cha, Jin Joo, Han, Jee Young, Han, Sang Youb, Cha, Dae Ryong
• Format: Article
• Language: English
• Subjects: 64/60; 692/163/2743/137/138; Animals; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; Diabetic Nephropathies - prevention & control; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Disease Models, Animal; Doxorubicin - toxicity; Inflammation Mediators - blood; Inflammation Mediators - urine; Kidney - drug effects; Kidney - injuries; Kidney - physiopathology; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Membrane Proteins - urine; Mice; Mice, Inbred C57BL; Osteopontin - biosynthesis; Osteopontin - genetics; Pathology; Piperazines - pharmacology; Podocytes - drug effects; Podocytes - pathology; Protective Agents - pharmacology; research-article
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2016.34

Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.