BioMedical Engineering Laboratory

Disease Mechanisms​

利用db/db與ACE2雙基因剔除小鼠探討RAS的調節對糖尿腎病病程的影響

        Diabetes is a main cause of chronic kidney disease(CKD)that is diabetic nephropathy. Diabetic nephropathy, accounting in uremic patients with 40~50%, is one of the most important basic and clinical biomedical research topic. It is known that renin-angiotensin system (RAS) disorder induced kidney inflammation, oxidative stress, structure and fibrotic pathogenesis may relate to the disease of diabetic nephropathy through ACE-Ang II/AT1R axis and ACE2-Ang-(1-7)/Mas axis. But there are still a lot of complex molecular and pathogenic mechanisms to be clarified. Among mechanisms, it is the most worth to be explored in the new functional enzymes within RAS, such as ACE2 (angiotensin conversing enzyme II) and chymase. The function of chymase is same as ACE (angiotensin conversing enzyme), however chymase can be tissue-specifically expressed and has a higher enzyme-specific activity for the conversion of Ang I to Ang II compared with ACE. In theory, chymase-dependent Ang II-generating function and ACE2 inhibitory or antagonistic ACE(Chymase)-Ang II/AT1R axis maybe play a significant role in the pathophysiologic progression of diabetic nephropathy.

        糖尿病為慢性腎臟疾病主要病因， 此糖尿腎病(diabetic nephropathy, DN) 約占尿毒症患者之 40~50%，是當今最重要的基礎與臨床生醫研究課題之一。已知腎素 -血管收縮素系統 (renin -angiotensin system, RAS)的失調，是DN重要病程之一，此即RAS中 ACE-Ang II/AT1R axis與 ACE2-Ang-(1 -7)/Mas axis對腎臟炎症反應與纖維化病變間有密切的關聯性。據此，本研究室進行一系列 in vivo小鼠模式實驗以深入探討之，我們同時欲瞭解針對ACE、chymase及ACE2的活性調節，是否能有效地減緩DN的病程發展。 我們的研究重點有：

  1. 建立 db/db 與 ACE2 雙基因剔除小鼠模式進行DN與 RAS途徑調節的相關性研究。
  2. 探討調節腎臟組織 探討調節腎臟組織中chymase活性以控制DN病程的效應。
  3. 探討 ACE2 與 ACE2 -AngAng -(1 -7)/Mas axis在 DN 病程發展中的角色。
  4. 探討合併調節ACE/chymase和 ACE2 活性是否能更有效、且顯著減緩 DN 的病程。

本項研究的長期目標為預防或治療 DN 新藥或療法提供基礎生醫科學之依據。

PM 2.5誘發慢性阻塞肺疾病(COPD)小鼠實驗模式之建立與探討

        COPD是一種因為肺部損傷導致漸進式肺部阻塞的慢性疾病，為全球第四大死亡疾病，在未來環境中PM2.5(空氣中小於2.5微米(um)之懸浮微粒)所引起的COPD不容小覷。流行病理學研究已漸確立PM2.5對於人體健康造成的影響，其中主要為提高呼吸道疾病與死亡的風險。本研究是在此項主題研究工作包括：

  1. 汙染空氣中PM2.5的收集與分析。
  2. PM2.5處理方式與劑量對實驗小鼠的影響。
  3. 探討實驗小鼠經 PM2.5處理後呼吸系統各組織的病理病程。

我們希望藉由本實驗動物模式的建立，日後可以據此與 臨床醫師擴大合作研究的範 圍，未來還將探討不同疾病 (例如高血脂、糖、高血壓之小鼠 )對 PM2.5刺激的敏感度。

Extracellular matrix remodeling in the atrial and ventricular tissues with heart diseases

        In heart, a proper balance between synthesis and degradation of extracellular matrix (ECM) is of utmost importance in maintaining normally physiological functions. Prolonged production of several cytokines induced by wound repair process, lasting shear stress or static pressure, and challenging by reactive oxygen species can lead to excessive ECM accumulation and chronic fibrosis, often resulting in organ failure. The interplay of matrix metalloproteinases (MMPs), a family of proteolytic enzymes responsible for ECM degradation, and its naturally endogenous inhibitor TIMPs have been demonstrated to play a pivotal role in ECM remodeling processes. The pathological imbalance of MMPs and TIMPs causing abnormally accumulating ECM and fibrotic lesions has been observed in the heart failure (HF), and also in pathological atria, such as atrial fibrillation (AF). Therefore, our lab performs the studies of new insights into the underlying mechanisms involved in ECM remodeling and balance of MMPs/TIMPs in the heart diseases.

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◎ The activities of MMP-2 and MMP-9 were analyzed by gelatin-zymography

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◎ The atrial tissues of fibrillating atria (AF) and sinus rhythmus (SR) were measured by in situ zymography

​​Selected publications related to this topic

  1. Hsieh WY, Chang TH, Chang HF, Chuang WH, Lu LC, Yang CW, Lin CS*, Chang CC. 2019. Renal chymase-dependent pathway for angiotensin II formation mediated acute kidney injury in a mouse model of aristolochic acid I-induced acute nephropathy. PLoS One. 14(1):e0210656. (IF=2.776, 24/69 in MULTIDISCIPLINARY SCIENCES)
  2. Chen CY, Wu VC, Lin CJ, Lin CS, Pan CF, Chen HH, Lin YF, Huang TM, Chen L, Wu CJ; National Taiwan University Study Group on Acute Renal Failure. 2018. Improvement in Mortality and End-Stage Renal Disease in Patients With Type 2 Diabetes After Acute Kidney Injury Who Are Prescribed Dipeptidyl Peptidase-4 Inhibitors. Mayo Clin Proc. 93(12):1760-1774. (IF=7.091, 12 of 160 in MEDICINE, GENERAL & INTERNAL)
  3. Cho CC, Hsieh WY, Tsai CH, Chen CY, Chang HF, Lin CS*. 2018. In vitro and in vivo experimental studies of pm2.5 on diseases progression. International Journal Environmental Research and Public Health. 15(7). pii: E1380. doi: 10.3390/ijerph15071380. (IF=2.468, 67/185 in PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH) 
  4. Lin CI, Tsai CH, Sun YL, Hsieh WY, Lin YC, Chen CY, Lin CS*. 2018. Instillation of particulate matter 2.5 induced acute lung injury and attenuated the injury recovery in ACE2 knockout mice. International Journal of Biological Sciences 14:253-265. doi:10.7150/ijbs.23489. (IF=4.067, 82/298 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
  5. Yang CW, Lu LC, Chang CC, Cho CC, Hsieh WY, Tsai CH, Lin YC, Lin CS*. 2017. Imbalanced plasma ACE and ACE2 level in the uremic patients with cardiovascular diseases and its change during a single hemodialysis session. Renal Failure 39:719-728.  (IF:1.687, 54/80 in UROLOGY & NEPHROLOGY)
  6. Hung YH, Hsieh WY, Hsieh JS, Liu FC, Tsai CH, Lu LC, Huang CY, Wu CL, Lin CS*. 2016. Alternative Roles of STAT3 and MAPK Signaling Pathways in the MMPs Activation and Progression of Lung Injury Induced by Cigarette Smoke Exposure in ACE2 Knockout Mice. International Journal of Biological Sciences 12:454-65. (IF=4.067, 82/298 in BIOCHEMISTRY & MOLECULAR BIOLOGY) Lu LC, Yang CW, Hsieh WY, Chuang WH, Lin YC, Lin CS*. 2016. Decreases in plasma MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in uremic patients during hemodialysis. Clinical and Experimental Nephrology 20:934-942. (IF=1.971, 46/80 in UROLOGY & NEPHROLOGY)
  7. Yang WJ, Liu FC, Hsieh JS, Chen CH, Hsiao SY, Lin CS*. 2015. Matrix metalloproteinase 2 level in human follicular fluid is a reliable marker of human oocyte maturation in in vitro fertilization and intracytoplasmic sperm injection cycles. Reproductive Biology and Endocrinology 13:102. (IF=2.589, 14/29 in REPRODUCTIVE BIOLOGY)
  8. ​Huang CH, Chang CC, Kuo CL, Huang CS, Lin CS*, Liu CS. 2015. Decrease in plasma cyclophilin a concentration at 1 month after myocardial infarction predicts better left ventricular performance and synchronicity at 6 months: A pilot study in patients with ST elevation myocardial infarction. International Journal of Biological Sciences 11: 38-47. doi: 10.7150/ijbs.10271 (IF=4.372, 72/291 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
  9. Huang CH, Chang CC, Kuo CL, Huang CS, Chiu TW, Lin CS*, Liu CS. 2014. Serum iron concentration, but not hemoglobin, correlates with TIMI risk score and 6-month left ventricular performance after primary angioplasty for acute myocardial infarction. Plos ONE 9(8):e104495. (IF=3.534, 8/55 inMULTIDISCIPLINARY SCIENCES)
  10. Huang CH, Chang CC, Huang CS, Kuo CL, Chen CP, Hsia CH, Chang YM, Chen HT, Feng CC, Lin LS, Yang PT, Tsai CD, Lin CS*, Liu CS. 2013. Using oxidized low-density lipoprotein autoantibodies to predict restenosis after balloon angioplasty in patients with acute myocardial infarction. PlosONE 8(10):e74726. (IF=3.534, 8/55 in MULTIDISCIPLINARY SCIENCES)
  11. Cheng KS, Liao YC, Chen MY, Kuan TC, Hong YH, Ko L, Hsieh WY, Chen MR, Lin CS*. 2013. Circulating matrix metalloproteinase-2 and -9 enzyme activities in the children with ventricular septal defect. International Journal of Biological Sciences 9(6):557-563. (IF=4.372, 72/291 inBIOCHEMISTRY & MOLECULAR BIOLOGY)
  12. Kuan TC, Chen MY, Liao YC, Ko L, Hong YH, Yen CY, Hsieh WY, Cheng KS, Wu CL, Lin CS*. 2013. Angiotensin II downregulates ACE2-mediated enhancement of MMP-2 activity in human cardiofibroblasts. Biochemistry and Cell Biology 91:1-8. (IF=2.350, 182/291 in BIOCHEMISTRY & MOLECULAR BIOLOGY)
  13. Kuo CE, Liang SF, Lu SS, Kuan TC, Lin CS*. 2013. Estimation and prediction of drug therapy on the termination of atrial fibrillation by autoregressive model with exogenous Inputs. IEEE Transactions on Information Technology in Biomedicine 17:153-161. (IF=2.072, 22/102 in COMPUTER SCIENCE, INFORMATION SYSTEMS)
  14. Hsieh WY, Kuan TC, Cheng KS, Liao YC, Chen MY, Lin PH, Hsu YC, Huang CY, Hsu WH, Yu SY, Lin CS*. 2012. ACE/ACE2 Ratio and MMP-9 Activity as Potential Biomarkers in Tuberculous Pleural Effusions. International Journal of Biological Sciences 8:1197-1205.
  15. Kuan TC, Yang TH, Wen CH, Chen MY, Lee IL, Lin CS*. 2011. Identifying the regulatory element for human angiotensin-converting enzyme 2 (ACE2) expression in human cardiofibroblasts. Peptides 32;1832-1839.
  16. Chang CC, Kuan TC, Hsieh YY, Ho YJ, Sun YL, Lin CS*. 2011. Effects of diosgenin on myometrial matrix metalloproteinase-2 and -9 activity and expression in ovariectomized rats. International Journal of Biological Sciences 7:837-847.
  17. Lin CS*, Pan CH, Wen CH, Yang TH, Kuan TC. 2010. Regulation of angiotensin converting enzyme II by angiotensin peptides in humancardiofibroblasts. Peptides 31:1334-1340.
  18. Lin LM, Lai LP, Lin CS, Chou NK, Chiu CY, Lin JL. Left ventricular extracellular matrix remodeling in dogs with right ventricular apical pacing.Journal of Cardiovascular Electrophysiology 2010:1142-1149.
  19. Chen CL, Huang SK, Lin JL, Lai LP, Lai SC, Liu CW, Chen WC, Wen CH, Lin CS*. 2008. Upregulation of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases in rapid atrial pacing-induced atrial fibrillation. Journal of Molecular and Cellular Cardiology 45:742-753.
  20. Lin CS*, Pan CH. 2008. Regulatory mechanisms of atrial fibrotic remodeling in atrial fibrillation. Cellular and Molecular Life Sciences 65:1489-1508.
  21. Pan CH, Wen CH, Lin CS*. 2008. Interplay of angiotensin II and angiotensin 1-7 in the regulations of matrix metalloproteinases of humancardiocytes. Experimental Physiology 93:599-612.
  22. Lin CS, Lai LP, Lin JL, Sun YL, Hsu CW, Chen CL, Mao SJT, Huang SKS. 2007. Increased expression of extracellular matrix proteins in rapid atrial pacing-induced atrial fibrillation. Heart Rhythm 4:938-949.
  23. Pan CH, Lin JL, Lai LP, Chen CL, Huang SKS, Lin CS*. 2007. Downregulation of angiotensin converting enzyme II is associated with pacing-induced sustained atrial fibrillation. FEBS Letters 581:526-534.
  24. Chen CL, Lin JL, Lai LP, Pan CH, Huang SKS, Lin CS*. 2007. Altered expression of FHL1, CARP, TSC-22 and P311 provide insights into complex transcriptional regulation in pacing-induced atrial fibrillation. Biochimica et Biophysica Acta 1772:317-329.