Brings Sebastian, Zhang Shaoping, Choong Yee S, Hogl Sebastian, Middleditch Martin, Kamalov Meder, Brimble Margaret A, Gong Deming, Cooper Garth J S
The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
Biochim Biophys Acta. 2015 Aug;1852(8):1610-8. doi: 10.1016/j.bbadis.2015.04.014. Epub 2015 Apr 18.
Advanced glycation end-products (AGEs) comprise a group of non-enzymatic post-translational modifications of proteins and are elevated in diabetic tissues. AGE-modification impairs the digestibility of collagen in vitro but little is known about its relation to collagen-degrading proteinases in vivo. N(ε)-carboxymethyllysine (CML) is a stable AGE that forms on lysyl side-chains in the presence of glucose, probably via a transition metal-catalysed mechanism. Here, rats with streptozotocin-induced diabetes and non-diabetic controls were treated for 8weeks with placebo or the Cu(II)-selective chelator, triethylenetetramine (TETA), commencing 8weeks after disease induction. Actions of diabetes and drug treatment were measured on collagen and collagen-degrading proteinases in kidney tissue. The digestibility and CML content of collagen, and corresponding levels of mRNAs and collagen, were related to changes in collagen-degrading-proteinases. Collagen-degrading proteinases, cathepsin L (CTSL) and matrix metalloproteinase-2 (MMP-2) were increased in diabetic rats. CTSL-levels correlated strongly and positively with increased collagen-CML levels and inversely with decreased collagen digestibility in diabetes. The collagen-rich mesangium displayed a strong increase of CTSL in diabetes. TETA treatment normalised kidney collagen content and partially normalised levels of CML and CTSL. These data provide evidence for an adaptive proteinase response in diabetic kidneys, affected by excessive collagen-CML formation and decreased collagen digestibility. The normalisation of collagen and partial normalisation of CML- and CTSL-levels by TETA treatment supports the involvement of Cu(II) in CML formation and altered collagen metabolism in diabetic kidneys. Cu(II)-chelation by TETA may represent a treatment option to rectify collagen metabolism in diabetes independent of alterations in blood glucose levels.
晚期糖基化终产物（AGEs）是一组蛋白质的非酶促翻译后修饰产物，在糖尿病组织中含量升高。AGE修饰会损害体外胶原蛋白的消化率，但关于其在体内与胶原蛋白降解蛋白酶的关系却知之甚少。N（ε）-羧甲基赖氨酸（CML）是一种稳定的AGE，在葡萄糖存在的情况下，可能通过过渡金属催化机制在赖氨酸侧链上形成。在此，将链脲佐菌素诱导的糖尿病大鼠和非糖尿病对照大鼠在疾病诱导8周后，用安慰剂或铜（II）选择性螯合剂三亚乙基四胺（TETA）治疗8周。测定糖尿病和药物治疗对肾组织中胶原蛋白和胶原蛋白降解蛋白酶的作用。胶原蛋白的消化率和CML含量，以及相应的mRNA和胶原蛋白水平，与胶原蛋白降解蛋白酶的变化有关。糖尿病大鼠中胶原蛋白降解蛋白酶组织蛋白酶L（CTSL）和基质金属蛋白酶-2（MMP-2）增加。在糖尿病中，CTSL水平与胶原蛋白CML水平的增加呈强正相关，与胶原蛋白消化率的降低呈负相关。富含胶原蛋白的系膜在糖尿病中CTSL显著增加。TETA治疗使肾脏胶原蛋白含量正常化，并部分使CML和CTSL水平正常化。这些数据为糖尿病肾脏中的适应性蛋白酶反应提供了证据，该反应受过量胶原蛋白CML形成和胶原蛋白消化率降低的影响。TETA治疗使胶原蛋白正常化以及CML和CTSL水平部分正常化，支持了铜（II）参与CML形成以及糖尿病肾脏中胶原蛋白代谢改变的观点。TETA对铜（II）的螯合可能代表一种纠正糖尿病中胶原蛋白代谢的治疗选择，而与血糖水平的变化无关。
