title: Targeting the AGE-RAGE axis improves renal function in the context of a healthy diet low in advanced glycation end-product content.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Diabetic mice given a low-AGE diet still developed renal disease, which could be attenuated by targeting of the AGE-RAGE axis.
authors.affiliation: Diabetes Complications Division, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia. vicki.thallas@bakeridi.edu.au
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas-Bonke
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.forename: Adeline Ly
authors.initials: AL
authors.lastname: Tan
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Harcourt
authors.forename: Philip E
authors.initials: PE
authors.lastname: Morgan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
authors.forename: Leon A
authors.initials: LA
authors.lastname: Bach
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
mesh_terms: D000818:Animals; D004032:Diet; D017127:Glycation End Products, Advanced / Q000008:administration & dosage*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*
chemical_list: D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic