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Hypertension: Shall We Focus associated with incident among women with- out diabetes. The authors prospectively studied 872 women on ? without diabetes or hypertension from the Nurses’ Health Study. After a follow-up of 14 years, 361 (41.4%) women Simona Bo and Paolo Cavallo-Perin developed hypertension. Plasma values were signif- Department of Internal Medicine, University of Turin, Turin, Italy icantly associated with incident hypertension: The highest resistin tertile conferred a 75% higher risk for hypertension J Am Soc Nephrol 21: 1067–1068, 2010. doi: 10.1681/ASN.2010050524 than the lowest (relative risk 1.75; 95% confidence interval 1.19 to 2.56). The relative risk did not substantially change after adjustment for multiple potential metabolic and nu- Adipose tissue is an active endocrine organ that produces sub- tritional confounding factors and for other adipokines. The stances having local and systemic actions on blood vessels, kid- risk was greater among older women. In a secondary analy- neys, and the . , , resistin, sis, inflammatory and endothelial biomarkers were mea- ␣ II, adipsin, TNF- , IGF-1, plasminogen-activator inhibitor 1, sured in a subset of women. Resistin levels were significantly and compose an incomplete list.1 associated with both groups of biomarkers. After further Resistin, an adipokine belonging to the cysteine-rich secre- adjustment for C-reactive , IL-6, soluble TNF recep- tory , was described as an adipocyte-derived tor 2, intercellular adhesion molecule 1, vascular adhesion polypeptide that links obesity and resistance in mice2; molecule 1, and E-selectin, resistin concentrations re- however, striking differences in the genomic organization and mained positively associated with an increased risk for inci- cellular source of resistin in rodents versus humans and the dent hypertension. highly contrasting results of human studies raise doubt about Increased resistin concentration may determine hyperten- its role as a mediator of human insulin resistance.3 Indeed, sion by its vasoconstrictive properties; the ability to promote human resistin expression is higher in mononuclear blood cell proliferation; and the increased expression cells and other nonadipocyte cells of adipose tissue than in of adhesion molecules, endothelin 1, metalloproteinases, and adipocytes.4 other mediators leading to .3,5,10,13 This protein might be involved in inflammation, either Moreover, in vitro analysis of expression in endothelial being induced by increased cytokine levels or directly stim- cells from human coronary showed that resistin is able ulating the production of proinflammatory cytokines, sug- to induce fatty acid–binding protein, a key molecule of insulin gesting that inflammation may be a hyperresistinemic resistance, diabetes, and atherosclerosis.13 Resistin may also state.5,6 Resistin associates with several markers of inflam- reduce vasorelaxation by pro-oxidant mechanisms: It could mation, including C-reactive protein, TNF-␣, and IL-6.5 increase superoxide radical production and decrease endothe- Resistin accumulates in the inflamed joints of patients with lial nitric oxide synthase expression, and these effects are re- rheumatoid arthritis, and its inflammatory effects are me- versed by treatment with antioxidants.9 Imbalance in the pro- diated by NF-␬B signaling pathways.7 Furthermore, resistin duction and regulation of oxygen radicals lead to oxidative activates human endothelial cells, which are therefore resis- stress, which is known to contribute to atherosclerosis.9 The tin-sensitive cells, leading to increased expression of adhe- participation of resistin in oxidative processes has been sug- sion molecules, and reduces -dependent and gested by the impact of oxidative stress on the regulation of independent vasorelaxation.3,8,9 Moreover, this protein adipokine gene expression and the effect of antioxidants on stimulates smooth muscle cell proliferation,10 and hypoxia resistin expression and concentrations in animals and hu- enhances resistin expression in vascular smooth muscle cell, mans.9,16 suggesting that resistin is implicated in the pathogenesis of Zhang et al.15 conclude that increased levels of resistin atherosclerosis under hypoxia.11 These effects could explain may exist in their nondiabetic population before the occur- the association found between higher circulating resistin levels rence of clinical hypertension; however, patients within the and increased prevalence of cardiovascular diseases and heart fail- highest resistin tertile showed significantly higher body mass ure in humans.5,12 index values, and it cannot be excluded that they also had A few studies have reported an association between hy- higher BP values at baseline, because hypertension in this co- perresistinemia and hypertension, in patients both with and hort was self-reported. Individuals with high-normal BP, even without diabetes.13,14 Zhang et al.15 now report in this issue when healthy, show reduced levels of adiponectin, increased of JASN that increased levels of resistin are significantly resistin concentrations, and early signs of endothelial dysfunc- tion and oxidative stress.14,17 Published online ahead of print. Publication date available at www.jasn.org. Hypertension results from a complex interaction of several

Correspondence: Dr. Simona Bo, Department of Internal Medicine, University pathophysiologic mechanisms. Among them, endothelial dys- of Turin, Corso Dogliotti 14, 10126 Turin, Italy. Phone: ϩ39-011-6967864; Fax: function, oxidative stress, increased vascular reactivity, and ϩ39-011-6634751; E-mail: [email protected] vascular remodeling may be causes or consequences of in- Copyright © 2010 by the American Society of Nephrology creased BP. The chicken or the egg is an old question; there-

J Am Soc Nephrol 21: 1063–1072, 2010 Editorials 1067 EDITORIALS www.jasn.org fore, it is difficult to determine whether increased concentra- resistin expression in cultured vascular smooth muscle cells under tions of resistin are the cause or the consequence of hypoxia. J Hypertens 26: 2349–2360, 2008 12. Frankel DS, Vasan RS, D’Agostino RB, Benjamin EJ, Levy D, Wang TJ, inflammation within the vascular wall, oxidative stress, or vas- Meigs JB: Resistin, adiponectin, and risk of heart failure: The Framing- cular dysfunction associated with hypertension. ham Offspring study. J Am Coll Cardiol 53: 754–762, 2009 Much needs to be learned about the relationship among 13. Takata Y, Osawa H, Kurata M, Kurokawa M, Yamauchi J, Ochi M, adipokines, inflammation, hypertension, and the cardiovascu- Nishida W, Okura T, Higaki J, Makino H: Hyperresistinemia is associ- lar system. Nevertheless, the study of Zhang et al.15 adds a piece ated with coexistence of hypertension and type 2 diabetes. Hyperten- sion 51: 534–539, 2008 to the emerging evidence that adipokines may contribute to 14. Papadopoulos DP, Makris TK, Krespi PG, Poulakou M, Stavroulakis G, the pathogenesis of chronic conditions. In the future, we Hatzizacharias AN, Perrea D, Votteas VV: Adiponectin and resistin should focus much more on the role of adipose tissue. Obesity plasma levels in healthy individuals with prehypertension. J Clin Hy- is a causative factor in the development of hypertension and is pertens 7: 729–733, 2005 linked to inflammation and chronic disease.18,19 15. Zhang L, Curhan GC, Forman JP: Plasma resistin levels associate with risk for hypertension among nondiabetic women. J Am Soc Nephrol Among implicated mechanisms such as increased re- 21: 1185–1191, 2010 tention, sleep disturbance, activation of the renin-angiotensin 16. Bo S, Ciccone G, Durazzo M, Gambino R, Massarenti P, Baldi I, Lezo system and sympathetic nervous system, and insulin resis- A, Tiozzo E, Pauletto D, Cassader D, Pagano G: Efficacy of anti- tance, the release of adipokines may play an adjunctive role in oxidant treatment in reducing resistin serum levels: A randomized the increased risk for hypertensive diseases. These molecules study. PLoS Clin Trials 2: e17, 2007 17. Bo S, Gambino R, Gentile L, Pagano G, Rosato R, Saracco GM, may provide incremental value in the prediction of cardiovas- Cassader M, Durazzo M, Cavallo-Perin P: High-normal cular risk beyond current schemes and approaches. is associated with a cluster of cardiovascular and metabolic risk factors: A population-based study. J Hypertens 27: 102–108, 2009 18. Ix JH, Sharma K: Mechanisms linking obesity, chronic kidney disease, and fatty disease: The roles of fetuin-A, adiponectin, and AMPK. DISCLOSURES J Am Soc Nephrol 21: 406–412, 2010 None. 19. Ramos LF, Shintani A, Ikizler TA, Himmelfarb J: Oxidative stress and inflammation are associated with adiposity in moderate to severe CKD. J Am Soc Nephrol 19: 593–599, 2008 REFERENCES

See related article, “Plasma Resistin Levels Associate with Risk for Hypertension 1. Wiçcek A, Kokot F, Chudek J, Adamczak M: The adipose tissue: A among Nondiabetic Women,” on pages 1185–1191. novel endocrine organ of interest to the nephrologist. Nephrol Dial Transplant 17: 191–195, 2002 2. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The resistin links obesity to Neighborhoods, Race, and diabetes. Nature 409: 307–312, 2001 3. Koerner A, Kratzsch J, Kiess W: Adipocytokines: Leptin—the classical, Nephrology Care resistin—the controversial, adiponectin—the promising, and more to come. Best Pract Clin Endocrinol Metab 19: 525–546, 2005 4. Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton Sharon Stein Merkin C, Macphee CH, Smith SA: Resistin is expressed in human macro- Division of Geriatrics, Geffen School of Medicine, University of Cali- phages and directly regulated by PPAR␥ activators. Biochem Biophys fornia, Los Angeles, Los Angeles, California Res Commun 300: 427–476, 2003 J Am Soc Nephrol 21: 1068–1070, 2010. 5. Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ: doi: 10.1681/ASN.2010050534 Resistin is an inflammatory marker of atherosclerosis in humans. Cir- culation 111: 932–939, 2005 6. Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA: An Access to nephrology care is essential to mitigating the progres- inflammatory cascade leading to hyperresistinemia in humans. PLoS 1 Med 1: e45, 2004 sion of renal failure. There is some evidence of racial dispari- 7. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A: Resistin, an ties with regard to this care, disparities whereby black individ- adipokine with potent proinflammatory properties. J Immunol 174: uals are less likely to received timely care compared with their 5789–5795, 2005 white counterparts.2 The underlying causes of these racial dif- 8. Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA: ferences are not fully understood but most likely include a Resistin promotes endothelial cell activation: Further evidence of adi- pokine-endothelial interactions. Circulation 108: 736–740, 2003 combination of socioeconomic and social factors. In this issue 9. Kougias P, Chai H, Lin PH, Yao Q, Lumsden AB, Yao Q, Chen C: Adipocyte-derived cytokine resistin causes endothelial dysfunction of Published online ahead of print. Publication date available at www.jasn.org. porcine coronary arteries. J Vasc Surg 41: 691–698, 2005 10. Calabro P, Samudio I, Willerson JT, Yeh ET: Resistin promotes smooth Correspondence: Dr. Sharon Stein Merkin, Division of Geriatrics, Geffen muscle cell proliferation through activation of extracellular signal- School of Medicine at UCLA, 10945 Le Conte Avenue, Suite 2339, Los Angeles, CA 90095-1687. Phone: 310-825-8253; Fax: 310-794-2199; E-mail: regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Cir- [email protected] culation 110: 3335–3340, 2004 11. Hung HF, Wang BW, Chang H, Shyu KG: The molecular regulation of Copyright © 2010 by the American Society of Nephrology

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