Received for publication April 18, 2005.
Revised June 7, 2005.
Accepted for publication June 7, 2005.

Early and sustained inhibition of Nuclear Factor kappa B prevents hypertension in spontaneously hypertensive rats

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 kappa B (NF-B). Therefore, the present study was designed to test the hypothesis that long-term inhibition of NF-B, 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-B inhibitor, pyrrolidine dithiocarbamate (PDTC) (100 mg.kg-1 daily intraperitoneally) to SHR from 7 weeks 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-B activation, elevated ICAM-1 and in situ mRNA MCP-1 expressions and interstitial accumulation of lymphocytes, macrophages and angiotensin-II-positive cells. PDTC administration prevented the rise in blood pressure, normalized renal cortical NF-B 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 which matched those found in the control WKY rats. Results suggest that NF-B-driven intrarenal inflammatory reactivity play a major role in the pathogenesis of hypertension in the SHR.

Key words: adhesion molecules, interstitial nephritis, lymphocytes, macrophage chemoattractant protein-1, macrophages, oxidative stress

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