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Long-Term Treatment of Glucagon-Like Peptide-1 Analog Exendin-4 Ameliorates Diabetic Nephropathy through Improving Metabolic Anomalies in db/db Mice

Cheol Whee Park^*, Hyeong Wook Kim^*, Seung Hyun Ko, Ji Hee Lim^*, Gyeong Ryul Ryu, Hyun Wha Chung^*, Sang Woo Han^*, Seog Jun Shin^*, Byung Kee Bang^*, Matthew D. Breyer and Yoon Sik Chang^*

^* Divisions of Nephrology and Endocrinology and Metabolism, Department of Internal Medicine, Catholic University of Korea, Seoul, Korea; and Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee

Address correspondence to: Dr. Yoon Sik Chang, Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, #62 Yoido-Dong, Youngdungpo-Ku, Seoul, Korea 150-713. Phone: +82-2-3779-1259; Fax: +82-2-786-7725; E-mail: ysc543{at}unitel.co.kr

Received for publication July 23, 2006. Accepted for publication January 31, 2007.

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone and is a new clinically available class of agents for improving of insulin resistance in both animals and humans with type 2 diabetes. These studies aimed to determine whether long-term treatment with a long-acting GLP-1 analog, exendin-4, delayed the progression of diabetes. Male db/db mice and db/m mice at 8 wk of age were treated with exendin-4 for 8 wk, whereas the control db/db mice received only vehicle. Urinary albumin excretion was significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in db/db mice that were treated with 0.5 nmol/kg exendin-4 and control db/db mice (P < 0.005). Intraperitoneal glucose tolerance test was improved in db/db mice that were treated with 1 nmol/kg exendin-4 compared with other groups (P < 0.05). Despite this, fasting blood glucose, glycated hemoglobin, and creatinine concentrations were not significantly different among db/db mice. Renal histology studies further demonstrated that glomerular hypertrophy, mesangial matrix expansion, TGF-1 expression, and type IV collagen accumulation and associated glomerular lipid accumulation were significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4. Furthermore, there were fewer infiltrating inflammatory cells and apoptotic cells in the glomeruli of db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in the other groups accompanied by an increase in the renal immunoreactivity of peroxisome proliferator–activated receptor and GLP-1 receptor–positive cells and a decrease in 24-h urinary 8-hydroxy-deoxyguanosine levels (P < 0.01, respectively) along with decreases in lipid content. Taken together, exendin-4 treatment seems to ameliorate diabetic nephropathy together with improvement of the metabolic anomalies. These results suggest that exendin-4 could provide a therapeutic role in diabetic nephropathy that results from type 2 diabetes.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673