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 TGFβ1, 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 TGFβ1, CD 147, and the p38 MAPK pathway.