Resveratrol increases AdipoR1 and AdipoR2 expression in type 2 diabetic nephropathy.
Adiponectin has multiple functions including insulin sensitization, anti-inflammation and antiatherogenesis in various organs. Adiponectin activates 5'-adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)α via the adiponectin receptor (AdipoR) 1 and 2, which are critical for regulating lipids and glucose homeostasis and for controlling oxidative stress. We investigated whether resveratrol can inhibit renal damage in type 2 diabetic db/db mice and the underlying mechanisms of its effects.



Four groups of male C57 BLKS/J db/m and db/db mice and human glomerular endothelial cells (HGECs) were used. Resveratrol was administered to diabetic and nondiabetic mice by oral gavage for 12 weeks starting at 8 weeks of age.



In db/db mice, resveratrol increased serum adiponectin levels and decreased albuminuria, glomerular matrix expansion, inflammation and apoptosis in the glomerulus. Resveratrol increased the phosphorylation of AMPK and silent information regulator T1 (SIRT1), and decreased phosphorylation of downstream effectors class O forkhead box (FoxO)1 and FoxO3a via increasing AdipoR1 and AdipoR2 in the renal cortex. Furthermore, resveratrol increased expression of PPARγ coactivator (PGC)-1α, estrogen-related receptor-1α, and phosphorylated acetyl-CoA carboxylase and decreased sterol regulatory element-binding protein 1. This effect lowered the content of nonesterified fatty acid and triacylglycerol in the kidneys, decreasing apoptosis, oxidative stress and activating endothelial nitric oxide synthase. Resveratrol prevented cultured HGECs from undergoing high-glucose-induced oxidative stress and apoptosis by activating the AMPK-SIRT1-PGC-1α axis and PPARα through increases in AdipoR1 and AdipoR2 expression.



These results suggest that resveratrol prevents diabetic nephropathy by ameliorating lipotoxicity, oxidative stress, apoptosis and endothelial dysfunction via increasing AdipoR1 and AdipoR2 expression.
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Hoon Suk
HS
Park
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Ji Hee
JH
Lim
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Min Young
MY
Kim
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Yaeni
Y
Kim
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
You Ah
YA
Hong
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Sun Ryoung
SR
Choi
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Sungjin
S
Chung
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Hyung Wook
HW
Kim
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Bum Soon
BS
Choi
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Yong Soo
YS
Kim
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Yoon Sik
YS
Chang
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. cheolwhee@hanmail.net.|Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, #505, Banpo-Dong, Seocho-Ku, Seoul, 137-040, Republic of Korea. cheolwhee@hanmail.net.
Cheol Whee
CW
Park
D000080242:8-Hydroxy-2'-Deoxyguanosine; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D054419:Receptors, Adiponectin / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D024141:Collagen Type IV; D005227:Fatty Acids; D051858:Forkhead Transcription Factors; D047493:PPAR alpha; D054419:Receptors, Adiponectin; D051780:Sterol Regulatory Element Binding Protein 1; D013267:Stilbenes; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; D051028:bcl-2-Associated X Protein; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; D000103:Acetyl-CoA Carboxylase; D003849:Deoxyguanosine; D000077185:Resveratrol
5′-adenosine monophosphate-activated protein kinase; Adiponectin; Diabetic nephropathy; Resveratrol