Shohei Yamada1, Jun Tanabe1, Yuji Ogura2, Yoshio Nagai3, Takeshi Sugaya1, Keiichi Ohata1, Yasunori Natsuki4, Daisuke Ichikawa1, Shiika Watanabe1, Kazuho Inoue5, Seiko Hoshino5, Kenjiro Kimura6, Yugo Shibagaki1, Atsuko Kamijo-Ikemori7,8. 1. Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan. 2. Department of Physiology, St. Marianna University School of Medicine, Kanagawa, Japan. 3. Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan. 4. Institute for Ultrastructural Morphology, St. Marianna University School of Medicine, Kawasaki, Japan. 5. Department of Anatomy, St. Marianna University School of Medicine, Kanagawa, Japan. 6. JCHO Tokyo Takanawa Hospital, Tokyo, Japan. 7. Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan. a2kamijo@marianna-u.ac.jp. 8. Department of Anatomy, St. Marianna University School of Medicine, Kanagawa, Japan. a2kamijo@marianna-u.ac.jp.
Abstract
BACKGROUND: The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders. METHODS: Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague-Dawley rats (n = 7) were injected only with a vehicle. RESULTS: The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment. CONCLUSIONS: Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.
BACKGROUND: The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders. METHODS: Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabeticSprague-Dawley rats (n = 7) were injected only with a vehicle. RESULTS: The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment. CONCLUSIONS: Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.
Authors: Melanie J Davies; Stephen C Bain; Stephen L Atkin; Peter Rossing; David Scott; Minara S Shamkhalova; Heidrun Bosch-Traberg; Annika Syrén; Guillermo E Umpierrez Journal: Diabetes Care Date: 2015-12-17 Impact factor: 19.112