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

• Published in: Diabetologia Vol. 51; no. 9; pp. 1741 - 1751
• Main Authors: 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, Cooper, G. J. S
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01-09-2008; Springer-Verlag; Springer
• Subjects: Albuminuria; Albuminuria - drug therapy; Animals; Associated diseases and complications; Biological and medical sciences; Chelating Agents - therapeutic use; Copper - therapeutic use; Diabetes Mellitus, Experimental - drug therapy; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - drug therapy; diabetic nephropathy; Disease Models, Animal; Divalent copper; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; extracellular matrix; Fibrosis; Glomerular hypertrophy; Human Physiology; Internal Medicine; Kidney - drug effects; Kidney - pathology; Kidney Glomerulus - drug effects; Kidney Glomerulus - pathology; Kidneys; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Nephrology. Urinary tract diseases; Rats; Semicarbazide-sensitive amine oxidase; SSAO; TGF-β; Transforming Growth Factor beta - antagonists & inhibitors; Trientine - therapeutic use; Triethylenetetramine; Urinary system involvement in other diseases. Miscellaneous; Glomerular hypertrophy; Semicarbazide-sensitive amine oxidase; Triethylenetetramine; SSAO; Diabetic nephropathy; Extracellular matrix; TGF-β; Albuminuria; Divalent copper; Endocrinopathy; Rat; Transforming growth factor β; Renal fibrosis; Kidney; Copper; Kidney disease; Urinary system disease; Diabetes mellitus; Rodentia; Concomitant disease; Vertebrata; Mammalia; Urinary system; Animal; Models; Hypertrophy
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-008-1088-7

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.