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ORIGINAL ARTICLEUric acid induces oxidative stress via an activationof the renin–angiotensin system in 3T3-L1 adipocytesJun-xia Zhang • Yu-ping Zhang • Qi-nan Wu •Bing ChenReceived: 11 November 2013/Accepted: 11 March 2014/Published online: 28 March 2014? Springer Science+Business Media New York 2014Abstract Hyperuricemia is recently reported involving invarious obesity-related cardiovascular disorders, especiallyhypertension. However, the underlying mechanisms are notcompletely understood. In the present study, we investi-gated whether uric acid upregulates renin–angiotensinsystem (RAS) expression in adipocytes. We also examinedwhether RAS activation plays a role in uric acid-inducedoxidative stress in adipocytes. The adipocytes of differentphenotypes were incubated with uric acid for 48 h,respectively. Losartan (10 -4 M) or captopril (10 -4 M) wasused to block adipose tissue RAS activation. mRNAexpressions of angiotensinogen (AGT), angiotensin-con-verting enzyme-1 (ACE-1), renin, angiotensin type 1receptor (AT1R), and angiotensin type 2 receptor (AT2R)were evaluated with real-time PCR. Angiotensin II con-centrations in supernatant were measured by ELISA.Intracellular reactive species (ROS) levels were measuredby f l uorescent probe DCFH-DA, DHR, or NBT assay. Theuric acid upregulated both RAS (AGT, ACE1, renin,AT1R, and AT2R) mRNA expressions and angiotensin IIprotein secretion and caused a signif i cant increase in ROSproduction in 3T3-L1 adipocytes. These effects could beprevented by RAS inhibitors, either losartan or captopril.RAS activation has been causally implicated in oxidativestress induced by uric acid in 3T3-L1 adipocytes, sug-gesting a plausible mechanism through which hyperurice-mia contributes to the pathogenesis of obesity-relatedcardiovascular diseases.Keywords Uric acid ? Oxidative stress ?Renin–angiotensin system ? AdipocytesIntroductionUric acid, the f i nal product of the purine metabolism, hasbeen the focus of concern because of its association withvarious cardiovascular diseases. Emerging evidences havesuggested that elevated uric acid levels are strongly asso-ciated with the occurrence and development of hyperten-sion [1]. Clinical studies have found that hyperuricemiarelates with elevated plasma renin activity in patients withhypertension [2, 3]. A model of mild hyperuricemia treatedwith uricase inhibitor developed hypertension after severalweeks due to uric acid-mediated renal vasoconstrictionwith an activation of the renin–angiotensin system (RAS)[4, 5]. The elevated blood pressure in rats was preventableby blockade of RAS with either enalapril or losartan [5].Consistent with these f i ndings, experimental studiesin vitro have also demonstrated that uric acid has directeffects on rat vascular smooth cell (VSMC) proliferation[6], human vascular endothelial cell (HVEC) dysfunction[7], and immortalized human mesangial cell (ihMC) pro-liferation [8] via local tissue RAS activation. Theseinvestigations indicate that the systemic RAS and localtissue RAS activated by uric acid may be partiallyresponsible for the possible pathogenetic role of uric acidinvolved in hypertension.Multiple lines of evidences indicate that obesity is cor-related with both systemic and adipose RAS overactivation[9]. Under pathophysiologic conditions, adipose-derivedRAS contributes to the development of obesity-relateddiseases, such as hypertension, diabetes, and atherosclero-sis [10]. As mentioned above, both uric acid and adiposeJ. Zhang ? Y. Zhang ? Q. Wu ? B. Chen (&)Department of Endocrinology and Metabolism, SouthwestHospital, Third Military Medical University, No. 30,Gaotanyanzheng Street, Shapingba District, Chongqing 400038,Chinae-mail: bingchen023@163.com123Endocrine (2015) 48:135–142DOI 10.1007/s12020-014-0239-5