Targeting the AGE-RAGE axis improves renal function in the context of a healthy diet low in advanced glycation end-product content

TY - JOUR

T1 - Targeting the AGE-RAGE axis improves renal function in the context of a healthy diet low in advanced glycation end-product content

AU - Thallas-Bonke, Vicki

AU - Coughlan, Melinda T

AU - Tan, Adeline Ly

AU - Harcourt, Brooke E

AU - Morgan, Philip E

AU - Davies, Michael Jonathan

AU - Bach, Leon A

AU - Cooper, Mark E

AU - Forbes, Josephine M

N1 - © 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - AIM: 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.METHODS: 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.RESULTS: 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.CONCLUSION: Diabetic mice given a low-AGE diet still developed renal disease, which could be attenuated by targeting of the AGE-RAGE axis.

AB - AIM: 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.METHODS: 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.RESULTS: 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.CONCLUSION: Diabetic mice given a low-AGE diet still developed renal disease, which could be attenuated by targeting of the AGE-RAGE axis.

KW - Animals

KW - Diet

KW - Glycosylation End Products, Advanced

KW - Kidney

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Receptors, Immunologic

U2 - 10.1111/j.1440-1797.2012.01665.x

DO - 10.1111/j.1440-1797.2012.01665.x

M3 - Journal article

C2 - 23046363

SN - 1320-5358

VL - 18

SP - 47

EP - 56

JO - Nephrology

JF - Nephrology

IS - 1

ER -