Diabetes-induced alterations in tissue collagen and carboxymethyllysine in rat kidneys: Association with increased collagen-degrading proteinases and amelioration by Cu(II)-selective chelation

作者：Brings Sebastian; Zhang Shaoping; Choong Yee S; Hogl Sebastian; Middleditch Martin; Kamalov Meder; Brimble Margaret A; Gong Deming; Cooper Garth J S^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2015, 1852(8): 1610-1618.

DOI：10.1016/j.bbadis.2015.04.014

• Advanced glycation end-product
• Autoxidative glycation
• Collagen
• Triethylenetetramine
• Matrix metalloproteinase-2
• Cathepsin L

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-epsilon-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 8 weeks with placebo or the Cu(II)-selective chelator, triethylenetetramine (TETA), commencing 8 weeks 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.

• 出版日期2015-8