title: Targeted reduction of advanced glycation improves renal function in obesity.
abstract: Obesity is highly prevalent in Western populations and is considered a risk factor for the development of renal impairment. Interventions that reduce the tissue burden of advanced glycation end-products (AGEs) have shown promise in stemming the progression of chronic disease. Here we tested if treatments that lower tissue AGE burden in patients and mice would improve obesity-related renal dysfunction. Overweight and obese individuals (body mass index (BMI) 26-39 kg/m(2)) were recruited to a randomized, crossover clinical trial involving 2 weeks each on a low- and a high-AGE-containing diet. Renal function and an inflammatory profile (monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF)) were improved following the low-AGE diet. Mechanisms of advanced glycation-related renal damage were investigated in a mouse model of obesity using the AGE-lowering pharmaceutical, alagebrium, and mice in which the receptor for AGE (RAGE) was deleted. Obesity, resulting from a diet high in both fat and AGE, caused renal impairment; however, treatment of the RAGE knockout mice with alagebrium improved urinary albumin excretion, creatinine clearance, the inflammatory profile, and renal oxidative stress. Alagebrium treatment, however, resulted in decreased weight gain and improved glycemic control compared with wild-type mice on a high-fat Western diet. Thus, targeted reduction of the advanced glycation pathway improved renal function in obesity.
authors.affiliation: Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia. brooke.harcourt@bakeridi.edu.au
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Harcourt
authors.forename: Karly C
authors.initials: KC
authors.lastname: Sourris
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.forename: Karen Z
authors.initials: KZ
authors.lastname: Walker
authors.forename: Sonia L
authors.initials: SL
authors.lastname: Dougherty
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
authors.forename: Amy L
authors.initials: AL
authors.lastname: Morley
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas-Bonke
authors.forename: Vibhasha
authors.initials: V
authors.lastname: Chand
authors.forename: Sally A
authors.initials: SA
authors.lastname: Penfold
authors.forename: Maximilian P J
authors.initials: MP
authors.lastname: de Courten
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Kingwell
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Barbora
authors.initials: B
authors.lastname: de Courten
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D018592:Cross-Over Studies; D004032:Diet; D017127:Glycation End Products, Advanced / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000178:diet therapy* / Q000188:drug therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000178:diet therapy* / Q000188:drug therapy / Q000503:physiopathology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013844:Thiazoles; C406794:alagebrium