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 (3mg/kg/day and 15mg/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.
Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Departments of Life Science, Tunghai University, Taichung, Taiwan; School of Medicine Chung Shan Medical University, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Shang-Feng
SF
Tsai
Departments of Animal Science and Biotechnology, Tunghai University, Taichung, Taiwan.
Chang-Chi
CC
Hsieh
Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; School of Medicine Chung Shan Medical University, Taiwan.
Ming-Ju
MJ
Wu
Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Departments of Life Science, Tunghai University, Taichung, Taiwan; School of Medicine Chung Shan Medical University, Taiwan.
Cheng-Hsu
CH
Chen
Department of Biomedical Sciences, Chung Shan Medical University, Taiwan.
Ting-Hui
TH
Lin
Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. Electronic address: d01230001@thu.edu.tw.
Mingli
M
Hsieh
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002478:Cells, Cultured; D021984:Cyclophilin A / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000652:urine; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D000069476:Linagliptin / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic
D054873:Dipeptidyl-Peptidase IV Inhibitors; D000069476:Linagliptin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D021984:Cyclophilin A; D003849:Deoxyguanosine
Cyclophilin A; Diabetic nephropathy; Dipeptidyl peptidase 4 inhibitors; Mesangial cell; Proximal tubular epithelial cell