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(Circulation. 2005;111:1962-1969.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Upregulation of Angiotensin II Type 1 Receptor, Inflammatory Mediators, and Enzymes of Arachidonate Metabolism in Obese Zucker Rat Kidney

Reversal by Angiotensin II Type 1 Receptor Blockade

Zhong-Gao Xu, MD, PhD; Linda Lanting, BS; Nosratola D. Vaziri, MD; Zhen Li, MD; Lili Sepassi, BA; Bernardo Rodriguez-Iturbe, MD; Rama Natarajan, PhD

From Gonda Diabetes Research Center (Z.-G.X., L.L., R.N.), Beckman Research Institute of the City of Hope, Duarte, Calif; Division of Nephrology and Hypertension (N.D.V., Z.L., L.S.), University of California at Irvine, Irvine, Calif; and Servicio Nephrologia (B.R.-I.), Hospital Universitario, Universidad del Zulia Maracaibo, Venezuela.

Correspondence to Rama Natarajan, PhD, Gonda Diabetes Research Center, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd, Duarte, CA 91010. E-mail rnatarajan{at}coh.org

Received November 10, 2004; revision received December 22, 2004; accepted December 28, 2004.

Background— Severe obesity can result in proteinuria and progressive glomerulosclerosis in humans and experimental animals. The associated renal disease is ameliorated by weight reduction and/or blockade of the renin-angiotensin system. Various growth factors, cytokines, and lipid mediators are implicated in the pathogenesis of renal disease. To explore the possible involvement of these mediators in obesity-induced renal disease, we examined the expression of key enzymes of arachidonate metabolism and inflammatory genes in untreated and losartan-treated obese Zucker rats, a model of obesity, insulin resistance, and renal injury.

Methods and Results— Seven-week-old male obese Zucker rats were randomized to losartan-treated (100 mg/L drinking H₂O) and untreated groups, with lean Zucker rats as controls. After 4 months, RNA and protein were obtained from renal cortical tissue for relative reverse transcription–polymerase chain reaction, Western blots, and immunohistochemistry. Compared with the lean controls, obese Zucker rats showed significant glomerular matrix expansion and increased mRNA expression of the extracellular matrix protein fibronectin, inflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, and 2 major enzymes of arachidonate metabolism, namely, 12/15-lipoxygenase and cyclooxygenase-2. This was associated with significant increases in p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase activities and marked upregulation of angiotensin II type 1 receptor (AT1R) mRNA and protein expression. These abnormalities and the associated glomerulopathy and proteinuria were prevented by administration of the AT1R blocker losartan.

Conclusions— These findings indicate that obesity-induced glomerulopathy is associated with upregulation of key inflammatory mediators. These events are associated with and perhaps in part due to upregulation of AT1R, as evidenced by their reversal with AT1R blocker treatment.

Key Words: obesity • angiotensin • inflammation • kidney

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