Metformin decreases high-fat diet-induced renal injury by regulating the expression of adipokines and the renal AMP-activated protein kinase/acetyl-CoA carboxylase pathway in mice.
Metabolic syndrome is characterized by insulin resistance, dyslipidemia and hypertension. These metabolic changes contribute to the development of obesity-induced kidney injury. AMP-activated protein kinase (AMPK) is a ubiquitous enzyme that is involved in the cellular metabolic response to metabolic stress. Metformin, an AMPK activator, has been reported to exert a protective effect against non-alcoholic steatohepatitis. However, little is known about its role in the pathogenesis of obesity-induced renal injury. The aim of this study was to investigate the effects of metformin on high-fat diet (HFD)-induced kidney injury. Obesity was induced by HFD (60% of total calories from fat, 20% protein and 20% carbohydrates) in 6-week-old C57BL/6 mice. Mice were fed HFD plus 0.5% metformin. The effects of metformin on HFD-induced renal injury were evaluated by determining metabolic parameters, serum adipokine levels and renal AMPK/acetyl-CoA carboxylase (ACC) activities, as well as a histological examination. HFD induced metabolic derangement, systemic insulin resistance and glomerular mesangial matrix expansion. The administration of metformin reduced HFD-induced metabolic derangement and renal injury. The administration of metformin reduced the HFD-induced increase in adipokine expression and macrophage infiltration. Moreover, renal AMPK activity, which was decreased by HFD, was recovered following the administration of metformin; in addition, fatty acid oxidation was increased by the inhibition of ACC. These results indicate that metformin exerts beneficial effects on obesity-induced renal injury by regulating systemic inflammation, insulin resistance and the renal AMPK/ACC pathway. The clinical application of metformin to obese or early diabetic patients may be helpful in preventing obesity- or diabetes-related kidney disease.
Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Deokjin-gu, Jeonju 561-712, Republic of Korea.
Dal
D
Kim
Jung Eun
JE
Lee
Yu Jin
YJ
Jung
Ae Sin
AS
Lee
Sik
S
Lee
Sung Kwang
SK
Park
Suhn Hee
SH
Kim
Byung-Hyun
BH
Park
Won
W
Kim
Kyung Pyo
KP
Kang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D054392:Adipokines / Q000097:blood / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D007333:Insulin Resistance; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010084:Oxidation-Reduction / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D054392:Adipokines; D053773:Transforming Growth Factor beta1; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase