Targeting the AGE-RAGE axis improves renal function in the context of a healthy diet low in advanced glycation end-product content
Article first published online: 17 DEC 2012
© 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology
Volume 18, Issue 1, pages 47–56, January 2013
How to Cite
Thallas-Bonke, V., Coughlan, M. T., Tan, A. L., Harcourt, B. E., Morgan, P. E., Davies, M. J., Bach, L. A., Cooper, M. E. and Forbes, J. M. (2013), Targeting the AGE-RAGE axis improves renal function in the context of a healthy diet low in advanced glycation end-product content. Nephrology, 18: 47–56. doi: 10.1111/j.1440-1797.2012.01665.x
- Issue published online: 17 DEC 2012
- Article first published online: 17 DEC 2012
- Accepted manuscript online: 10 OCT 2012 06:03AM EST
- Manuscript Accepted: 3 OCT 2012
- Victorian Government's OIS Program
- Juvenile Diabetes Research Foundation (JDRF)
- National Health and Medical Research Council of Australia
- JDRF Career Development Award
- JDRF Advanced Postdoctoral Fellowship
- advanced glycation end-product;
- diabetic nephropathy;
- low-AGE diet;
- RAGE deletion;
- receptor for advanced glycation end-product
Mouse chow is commonly high in advanced glycation end-products, known contributors to diabetic nephropathy. The aim of this study was to evaluate if targeting of the AGE-RAGE axis was still effective in the context of a diet low in AGE content, which is more comparable to diets consumed by individuals with type 1 diabetes.
C57BL/6J wild-type and mice deficient in the receptor for AGEs (RAGE-KO) consumed a diet low in AGE content. Groups of mice were given (i) vehicle; (ii) streptozotocin; or (iii) streptozotocin + AGE lowering therapy (alagebrium chloride) and followed for 24 weeks.
Diabetic mice had high urinary albumin excretion rates, hyperfiltration and release of urinary Kim-1, not seen in diabetic RAGE-KO mice. Diabetic mice also had renal fibrosis, measured by glomerulosclerosis, tubulointerstitial expansion, TGF-β1 and glomerular collagen-IV deposition which almost all improved by RAGE-KO or alagebium. Diabetic mice had a greater renal burden of AGEs and increased expression of renal specific PKC-α phosphorylation, which was improved in RAGE-KO mice, or those treated with alagebrium.
Diabetic mice given a low-AGE diet still developed renal disease, which could be attenuated by targeting of the AGE-RAGE axis.