Original Report: Laboratory Investigation

Effects of Dietary Salt on Intrarenal Angiotensin System, NAD(P)H Oxidase, COX-2, MCP-1 and PAI-1 Expressions and NF-B Activity in Salt-Sensitive and -Resistant Rat Kidneys
G. Chandramohan^{a, b}, Y. Bai^c, K. Norris^{a, b}, B. Rodriguez-Iturbe^{d, e}, N.D. Vaziri<sup>c

a</sup>Charles R. Drew University of Medicine and Science and
^bKing Drew Medical Center, Los Angeles, Calif., and
^cDivision of Nephrology and Hypertension, University of California, Irvine, Calif., USA;
^dRenal Service, Hospital Universitario, Universidad del Zulia, and
^eCentro de Investigaciones Biomédicas, IVIC-Zuli, Maracaibo, Venezuela

Address of Corresponding Author

Am J Nephrol 2008;28:158-167 (DOI: 10.1159/000110021)

  Key Words

• Hypertension
• Oxidative stress
• Inflammation
• Renal injury
• Dietary sodium
• Renin-angiotensin system
• Cardiovascular disease

  Abstract

Background: Chronic consumption of a high-salt diet causes hypertension (HTN) and renal injury in Dahl salt-sensitive (SSR) but not salt-resistant rats (SRR). These events are, in part, mediated by oxidative stress and inflammation in the kidney and vascular tissues. Activation of the angiotensin II type 1 (AT₁) receptor plays an important role in the pathogenesis of oxidative stress and inflammation in many hypertensive disorders. However, the systemic renin-angiotensin system (RAS) is typically suppressed in salt-sensitive HTN. This study was designed to test the hypothesis that differential response to a high-salt diet in SSR versus SRR may be related to upregulation of tissue RAS and pathways involved in inflammation and reactive oxygen species (ROS) production. Methods and Results: SSR and SRR were studied 3 weeks after consumption of high- (8%) or low-salt (0.07%) diets. The SSR consuming a low-salt diet exhibited significant increases in AT₁ receptor, cyclooxygenase (COX) 2, plasminogen activator inhibitor (PAI) and phospho-IB in the kidney as compared to those found in SRR. The high-salt diet resulted in severe HTN and proteinuria (in SSR but not SRR) and marked elevations of renal tissue monocyte chemoattractant protein 1, p22^phox, NADPH oxidase subunit 4, angiotensin-II-positive cell count, infiltrating T cells and macrophages and further increases in AT₁ receptor, COX-2, PAI-1 and phospho-IB in the SSR group. The high-salt diet significantly lowered plasma renin activity (PRA) in SRR but not in the SSR. COX-1 abundance was similar on the low-salt diet and rose equally with the high-salt diet in both groups. Among subgroups of animals fed the low-salt diet, kidney glutathione peroxidase (GPX) abundance was significantly lower in the SSR than SRR. The high-salt diet raised GPX and mitochondrial superoxide dismutase (SOD) abundance in the SRR kidneys but failed to do so in SSR. Cu/Zn-SOD abundance was similar in the subgroups of SSR and SRR fed the low-salt diet. The high-salt diet resulted in downregulation of Cu/Zn-SOD in SSR but not SRR. Conclusions: Salt sensitivity in the SSR is associated with upregulations of the intrarenal angiotensin system, ROS-generating and proinflammatory/profibrotic proteins and an inability to raise antioxidant enzymes and maximally suppress PRA in response to high salt intake. These events can contribute to renal injury with high salt intake in SSR.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

N.D. Vaziri, MD
Division of Nephrology and Hypertension, UCI Medical Center
101 The City Drive, Bldg 53, Rm 125, Rt 81
Orange, CA 92868 (USA)
Tel. +1 714 456 5142, Fax +1 714 456 6034, E-Mail ndvaziri@uci.edu

  Article Information

Received: June 22, 2007
Accepted: September 4, 2007
Published online: October 19, 2007
Number of Print Pages : 10
Number of Figures : 7, Number of Tables : 1, Number of References : 46