A copper(II)-selective chelator ameliorates diabetes-evoked renal fibrosis and albuminuria, and suppresses pathogenic TGF-β activation in the kidneys of rats used as a model of diabetes

Journal article

Gong, D., Lu, J., Chen, X., Reddy, S., Crossman, D. J., Glyn-Jones, S., Choong, Y.-S., Kennedy, J., Barry, B., Zhang, S., Chan, Y.-K., Ruggiero, K., Phillips, A. R. J. and Cooper, G. J. S.. (2008). A copper(II)-selective chelator ameliorates diabetes-evoked renal fibrosis and albuminuria, and suppresses pathogenic TGF-β activation in the kidneys of rats used as a model of diabetes. Diabetologia. 51(9), pp. 1741-1751. https://doi.org/10.1007/s00125-008-1088-7
AuthorsGong, D., Lu, J., Chen, X., Reddy, S., Crossman, D. J., Glyn-Jones, S., Choong, Y.-S., Kennedy, J., Barry, B., Zhang, S., Chan, Y.-K., Ruggiero, K., Phillips, A. R. J. and Cooper, G. J. S.
Abstract

Aims/hypothesis
The selective CuII chelator triethylenetetramine (TETA) extracts systemic CuII into the urine of diabetic humans and rats as a model of diabetes, and in the process also normalises hallmarks of diabetic heart disease. However, the role of Cu and its response to TETA in animals with diabetic nephropathy were previously unknown. Here, we report the effects of TETA treatment on Cu and other essential elements, as well as on indices of renal injury and known pathogenic molecular processes, in kidneys from a rat model of diabetes.

Methods
Rats at 8 weeks after streptozotocin-induction of diabetes were treated with oral TETA (34 mg/day in drinking water) for a further 8 weeks and then compared with untreated diabetic control animals.

Results
Renal tissue Cu was substantively elevated by diabetes and normalised by TETA, which also suppressed whole-kidney and glomerular hypertrophy without lowering blood glucose. The urinary albumin: creatinine ratio was significantly elevated in the rat model of diabetes but lowered by TETA. Total collagen was also elevated in diabetic kidneys and significantly improved by TETA. Furthermore, renal cortex levels of TGF-β1, MAD homologue (SMAD) 4, phosphorylated SMAD2, fibronectin-1, collagen-III, collagen-IV, plasminogen activator inhibitor-1 and semicarbazide-sensitive amine oxidase all tended to be elevated in diabetes and normalised by TETA.

Conclusions/interpretation
Dysregulation of renal Cu homeostasis may be a key event eliciting development of diabetic nephropathy. Selective CuII chelation can protect against pathogenic mechanisms that lead to or cause diabetic nephropathy and might be clinically useful in the treatment of early-stage diabetic kidney disease.

Keywordsalbuminuria; diabetic nephropathy; divalent copper; extracellular matrix; glomerular hypertrophy; semicarbazide-sensitive amine oxidase; SSAO; TGF-β; triethylenetetramine
Year2008
JournalDiabetologia
Journal citation51 (9), pp. 1741-1751
PublisherSpringer
ISSN0012-186X
Digital Object Identifier (DOI)https://doi.org/10.1007/s00125-008-1088-7
PubMed ID18636238
Scopus EID2-s2.0-49249098236
Page range1741-1751
Publisher's version
License
All rights reserved
File Access Level
Controlled
Output statusPublished
Publication dates
Online18 Jul 2008
Publication process dates
Accepted21 May 2008
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Copper(ii)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: Comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments
Lu, J., Gong, D., Choong, Y. S., Xu, H., Chan, Kai, Chen, X., Fitzpatrick, S., Glyn-Jones, S., Zhang, S., Nakamura, T., Ruggiero, K., Obolonkin, V., Poppitt, S. D., Phillips, A. R. J. and Cooper, G. J. S.. (2010). Copper(ii)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: Comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments. Diabetologia. 53(6), pp. 1217 - 1226. https://doi.org/10.1007/s00125-010-1698-8
No evidence of an effect of alterations in dietary fatty acids on fasting adiponectin over 3 weeks
Lithander, Fiona E., Keogh, Geraldine F., Wang, Yu, Cooper, G. J. S., Mulvey, Tom B., Chan, Kai, McArdle, Brian H. and Poppitt, S D.. (2008). No evidence of an effect of alterations in dietary fatty acids on fasting adiponectin over 3 weeks. Obesity. 16(3), pp. 592 - 599. https://doi.org/10.1038/oby.2007.97
Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-alpha, and C-reactive protein to a high-fat dietary load
Poppitt, S. D., Keogh, Geraldine F., Lithander, Fiona E., Chan, Kai, Wang, Yu, Mulvey, Tom B., McArdle, Brian H. and Cooper, G J. S.. (2008). Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-alpha, and C-reactive protein to a high-fat dietary load. Nutrition. 24(4), pp. 322 - 329. https://doi.org/10.1016/j.nut.2007.12.012
Triethylenetetramine and metabolites: levels in relation to copper and zinc excretion in urine of healthy volunteers and type 2 diabetic patients
Lu, Jun, Chan, Kai, Gamble, Gregory D., Poppitt, S D., Othman, Asma A. and Cooper, G. J. S.. (2007). Triethylenetetramine and metabolites: levels in relation to copper and zinc excretion in urine of healthy volunteers and type 2 diabetic patients. Drug Metabolism and Disposition. 35(2), pp. 221 - 227. https://doi.org/10.1124/dmd.106.012922
Practicum in Teacher Education :Implications for School Leaders
Kennedy, Joy and Dorman, Jeffrey Paul. (2007). Practicum in Teacher Education :Implications for School Leaders. Directions for Catholic Educational Leadership in the 21st Century: The vision, challenges and reality: Proceedings of the 2007 International Conference on Catholic Educational leadership. Sydney, Australia: Australian Catholic University. pp. 1 - 33
Determination of triethylenetetramine (TETA) and its metabolites in human plasma and urine by liquid chromatography-mass spectrometry (LC-MS)
Lu, Jun, Chan, Kai, Poppitt, S. D. and Cooper, G J. S.. (2007). Determination of triethylenetetramine (TETA) and its metabolites in human plasma and urine by liquid chromatography-mass spectrometry (LC-MS). Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. 859(1), pp. 62 - 68. https://doi.org/10.1016/j.jchromb.2007.09.001
Professional Partnerships in Teacher Education :Implications for practice from an Australian learning environment study
Kennedy, Joy. (2007). Professional Partnerships in Teacher Education :Implications for practice from an Australian learning environment study. In Dr R Mark - Director of Research Queens University Belfast (Ed.). 37th Annual SCUTREA Conference. Leeds,United Kingdom: Standing Conference on University Teaching and Res.... pp. 1 - 10
A study of learning environment in the extended practicum of a pre-service teacher education course at a Catholic University
Kennedy, Joy. (2006). A study of learning environment in the extended practicum of a pre-service teacher education course at a Catholic University [Thesis]. https://doi.org/10.4226/66/5a94bb025e4dd
Effect of high-fat meals and fatty acid saturation on postprandial levels of the hormones ghrelin and leptin in healthy men
Poppitt, S. D., Leahy, F. E., Keogh, G. F., Wang, Y, Mulvey, T B., Stojkovic, M, Chan, Kai, Choong, Y S., McArdle, B H. and Cooper, G. J. S.. (2006). Effect of high-fat meals and fatty acid saturation on postprandial levels of the hormones ghrelin and leptin in healthy men. European Journal of Clinical Nutrition. 60(1), pp. 77 - 84. https://doi.org/10.1038/sj.ejcn.1602270
Molecular changes evoked by triethylenetetramine treatment in the extracellular matrix of the heart and aorta in diabetic rats
Gong, Deming, Lu, Jun, Chen, Xiuyin, Choong, Soon Y., Zhang, Shaoping, Chan, Kai, Glyn-Jones, Sarah, Gamble, Gregory D., Phillips, Anthony R. J. and Cooper, Garth J. S.. (2006). Molecular changes evoked by triethylenetetramine treatment in the extracellular matrix of the heart and aorta in diabetic rats. Molecular Pharmacology. 70(6), pp. 2045 - 2051. https://doi.org/10.1124/mol.106.028605
Demonstratuon of hyperglycemia-driven pathogenic abnormality of copper homeostasis in diabetes and its reversibility by selective chelation
Cooper, G. J. S., Chan, Kai, Dissanayake, Ajith M., Leahy, Fiona E., Keogh, Geraldine F., Frampton, Chris M., Gamble, Gregory D., Brunton, Dianne H., Baker, John R. and Poppitt, S D.. (2005). Demonstratuon of hyperglycemia-driven pathogenic abnormality of copper homeostasis in diabetes and its reversibility by selective chelation. Diabetes. 54(5), pp. 1468 - 1476.
Regeneration of the heart in diabetes by selective copper chelation
Cooper, G. J. S., Phillips, Anthony R. J., Choong, Soon Y., Leonard, Bridget L., Crossman, David J., Brunton, Dianne H., Saafi, Etuate L., Dissanayake, Ajith M., Cowan, Brett R., Young, Alistair A., Occleshaw, Christopher J., Chan, Kai, Leahy, Fiona E., Keogh, Geraldine F., Gamble, Gregory D., Allen, Grant R., Pope, Adele J., Boyd, Peter D. W., Poppitt, S D., ... Baker, John R.. (2004). Regeneration of the heart in diabetes by selective copper chelation. Diabetes. 53(9), pp. 2501 - 2508.
Development and validation of the extended practicum learning environment inventory
Dorman, Jeffrey Paul and Kennedy, Joy. (2002). Development and validation of the extended practicum learning environment inventory. In J. Reid and T. Brown (Ed.). Challenging Futures: Changing Agendas in Teacher Education. Armidale, Australia: University of New England.