Novel findings of secreted cyclophilin A in diabetic nephropathy and its association with renal protection of dipeptidyl peptidase 4 inhibitor

Background: Our previous clinical indicated that urinary cyclophilin A was a good marker for diabetic nephropathy. Methods: We used animal and cell models of diabetic nephropathy to examine the role of cyclophilin A in disease progression. Results: Significantly increased urinary cyclophilin A could be detected in db/db at the 8th week Linagliptin (3 mg/ kg/day and 15 mg/kg/day) could suppress urinary 8-hydroxy-2'-deoxyguanosine at the 8th and 16th week but only the high dose Linagliption could suppress cyclophilin A at the 8th week. Compared to 8-hydroxy-2'deoxyguanosine, cyclophilin A was a stronger, earlier, and more sensitive marker. Immunohistochemical staining for cyclophilin A was also positive for db/db. In cell studies, oxidative stress and hyperglycemia could stimulate MES-13 and HK-2 cells to secrete cyclophilin A. Hyperglycemia stimulated HK-2 cells to secrete TGF beta 1, which caused secretion of cyclophilin A. The secreted cyclophilin A further stimulated CD 147 to move outward from cytosol onto cell membrane in confocal microscopy, which was associated with the p38 MAPK pathway in the downstream. Conclusions: Secreted cyclophilin A may play an important role in diabetic nephropathy in the mouse model and is associated with TGM1, CD 147, and the p38 MAPK pathway. (C) 2016 Elsevier B.V. All rights reserved.