Glomerulosclerosis is a key element in end-stage renal failure. AngiotensinII (AngII) plays an important role in modulating cell growth and extracellular matrix (ECM) synthesis and degradation. Adiponectin, a protein derived from adipocytes, is primarily involved in regulating glucose levels and fatty acid break down. It has recently been shown to have antiatherosclerotic and anti-inflammatory properties. However, the role of adiponectin as a renoprotective agent has not been fully explored. We herein examine the effect of adiponectin on AngII-induced TGF1 and ECM production in human renal mesangial cells (HRMCs) and explore the signaling pathway involved. In this study, we found that both adiponectin receptor 1 and adiponectin receptor 2 are expressed in HRMCs. Adiponectin (10 g/mL) attenuated the stimulatory effect of AngII on TGF-1 and fibronectin. Furthermore, adiponectin activated the AMP-activated protein kinase (AMPK), and the AMPK-specific inhibitor (compound C) blocked AMPK activation. We also determined that compound C blocked the inhibitory effect of adiponectin on AngII-stimulated TGF1 and fibronectin production. In summary, these results demonstrate that adiponectin suppresses AngII-induced synthesis of ECM in mesangial cells via activation of the AMPK pathway. Based on our data, we suggest that this mechanism could delay the progression of kidney disease. (C) 2014 International Union of Biochemistry and Molecular Biology, Inc.