The Role of Secreted Cyclophilin A in Diabetic Nephropathy

• Main Authors: TSAI, SHANG-FENG, 蔡尚峰
• Other Authors: HSIEH, MINGLI
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/63067822971514688814

博士 === 東海大學 === 生命科學系 === 105 === Type 2 diabetes mellitus (DM) is the most common single cause of end-stage renal disease (ESRD). In spite of many modern therapies of glycemic and blood pressure control for DM, many patients continue to experience progressive renal damage. Thus, researches involving new markers and a more detailed molecular pathway of DN are beneficial to treatment. Cyclophilin A (CypA) is an 18-kD protein and the secreted form of CypA (sCypA) was reported to correlate with cardiovascular diseases (CVD). Patients with CVD have more secretion of CypA, which stimulate the ERK1/2, Akt and JAK pathway. The connection between DN and sCypA has never been elucidated before this study, which aims to investigate sCypA's correlation with renal dysfunction and the associated molecular pathway. In addition, we examined closely at the renal protection effects of Linagliptin (BI-1356, Trajenta), a dipeptidyl peptidase 4 inhibitors (DPP-4i), and determined potential association between Linagliptin and sCypA. In the human study, a total of 100 DN patients and 20 healthy control subjects were enrolled. The concentration of urinary CypA correlated well with the progression of renal function and a significant increase in urinary CypA was noted in stage 2 DN (p=0.012) and persisted in later stages. We could diagnose stage 2 DN using urinary CypA with a sensitivity of 90.0% and specificity of 72.7%. The area under curve was up to 0.85, indicating a good discriminatory power. Thus, urinary CypA is a good marker for DN. The mouse model exhibited a higher concentration of urinary sCypA and8-hydroxy-2' –deoxyguanosine (8OHdG) in db/db groups, both substances were detected as early as the 8th week up to the 16th week. Our results indicated that the sCypA is a better, stronger and more sensitive indicator for DN than 8OHdG. In the cell models, Hyperglycemia and oxidative stress both can stimulate mesangial cell (MES-13) and proximal tubular epithelial cells (HK-2) to secret CypA. Hyperglycemia stimulated HK-2 cells to secrete TGFβ1, which caused secretion of CypA. The sCypA 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. According to human, mouse and cellular studies, we proved CypA is a good marker for DN. Secreted CypA is also associated with the pathogenesis of DN. Besides, renal protection of Linaglitpin is associated with this pathway.