Abstract
Compelling evidence has emerged pointing to the interaction of oxidative stress and renal interstitial inflammation and their mutual contribution to the pathogenesis of hypertension in experimental animals. Renal interstitial inflammation in spontaneously hypertensive rats (SHR) is accompanied by and largely due to activation of redox-sensitive, proinflammatory nuclear transcription factor-κB (NF-κB). Therefore, the present study was designed to test the hypothesis that long-term inhibition of NF-κB, beginning early in the course of the disease, may attenuate renal interstitial inflammation and hypertension in SHR. To this end, we administered the reputed NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) (100 mg/kg daily intraperitoneally) to SHR from 7 to 25 weeks of age and compared the results with vehicle-treated SHR. Vehicle-treated and PDTC-treated Wistar Kyoto (WKY) rats served as controls. The untreated SHR exhibited a significant rise in arterial pressure; increased NF-κB activation, elevated intercellular adhesion molecule (ICAM)-1 and in situ mRNA macrophage chemoattractant molecule-1 (MCP-1) expressions; and interstitial accumulation of lymphocytes, macrophages, and angiotensin-II-positive cells. PDTC administration prevented the rise in blood pressure, and normalized renal cortical NF-κB activity as well as ICAM-1 and MCP-1 expressions. This was accompanied by a significant reduction in infiltration of immune cells, angiotensin II-expressing cells, and renal tissue malondialdehyde content to values that matched those found in the control WKY rats. Results suggest that NF-κB-driven intrarenal inflammatory reactivity play a major role in the pathogenesis of hypertension in the SHR.
Footnotes
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Financial support for this study was provided by a grant from the Asociación de Amigos del Riñón (Maracaibo) and Fondo Nacional de Ciencia y Tecnología Grant S1-2001001097 (Venezuela). A.F. and V.V. are recipients of grants from the Asociación de Amigo del Riñon, Maracaibo, Venezuela.
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doi:10.1124/jpet.105.088062.
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ABBREVIATIONS: SHR, spontaneously hypertensive rats; NF-κB, nuclear transcription factor-κB; PDTC, pyrrolidine dithiocarbamate; dTGR, double transgenic rat; WKY, Wistar Kyoto; MCP-1, macrophage chemoattractant molecule-1; MDA, malondialdehyde; DEPC, diethyl pyrocarbonate; SSC, standard saline citrate; ICAM, intercellular adhesion molecule; NO, nitric oxide; iNOS, inducible nitric-oxide synthase.
- Received April 15, 2005.
- Accepted June 7, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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