title: Adiponectin attenuates angiotensin II-induced oxidative stress in renal tubular cells through AMPK and cAMP-Epac signal transduction pathways.
abstract: Obesity is a risk factor for chronic kidney disease (CKD) progression. Circulating levels of adiponectin, an adipokine, decrease with obesity and play a protective role in the cardiovascular system. We hypothesized that adiponectin might also protect the kidney. Because activation of the renin-angiotensin system (RAS) is a contributor to CKD progression, we tested our hypothesis by studying the interactions between adiponectin and angiotensin II (ANG II) in renal tubular cells. Primary human renal proximal tubule cells expressed both adiponectin receptor 1 and 2 (adipoR1 and R2). ANG II-induced NADPH oxidase activation and oxidative stress were attenuated by adiponectin and dependent on adipoR1. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) mimicked, while inhibition of AMPK with compound C abrogated, the effect of adiponectin on ANG II-induced activation of NADPH oxidase. Similarly, the effect of adiponectin was recapitulated by the stable cAMP analogs 4-chlorophenylthio (pCPT)-cAMP and dibutyryl (db)-cAMP and blocked by the adenylate cyclase inhibitor SQ22536. Adiponectin did not activate PKA in renal tubular cells, and the specific PKA inhibitor myristoylated PKI (14-22) amide failed to block the inhibitory effect of adiponectin on ANG II-induced NADPH oxidase activation. In contrast, the specific Epac activator 8-(4-chlorophenylthio)-2'-O-methyl (8-CPT-2-O-Me)-cAMP blocked ANG II-induced activation of NADPH oxidase, an effect that was reversed by coincubation with the AMPK inhibitor compound C. Finally, adiponectin attenuated ANG II-induced NF-κB activation and fibronectin protein expression. These in vitro findings support the hypothesis that adiponectin may attenuate the deleterious effects of ANG II in the kidney and play a protective role in CKD.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.forename: George C
authors.initials: GC
authors.lastname: Liu
authors.forename: Crystal
authors.initials: C
authors.lastname: Kim
authors.forename: Rana
authors.initials: R
authors.lastname: Yassa
authors.forename: Joyce
authors.initials: J
authors.lastname: Zhou
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D052242:Adiponectin / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology* / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000037:antagonists & inhibitors; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D054419:Receptors, Adiponectin / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000517:prevention & control; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D052242:Adiponectin; D004791:Enzyme Inhibitors; D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; D016328:NF-kappa B; D011720:Pyrazoles; D011743:Pyrimidines; C116122:RAPGEF3 protein, human; D054419:Receptors, Adiponectin; C516138:dorsomorphin; D000804:Angiotensin II; D000242:Cyclic AMP; D019255:NADPH Oxidases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; adipokine; cAMP; chronic kidney disease; obesity