Early and sustained inhibition of nuclear factor-kappaB prevents hypertension in spontaneously hypertensive rats.
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-kappaB (NF-kappaB). Therefore, the present study was designed to test the hypothesis that long-term inhibition of NF-kappaB, 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-kappaB 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-kappaB 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-kappaB 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-kappaB-driven intrarenal inflammatory reactivity play a major role in the pathogenesis of hypertension in the SHR.
Rodríguez-Iturbe
Bernardo
B
Renal Service, Hospital Universitario, Universidad del Zulia, Instituto de Investigaciones Biomédicas, Maracaibo, Venezuela. bernardori@telcel.net.ve
Ferrebuz
Atilio
A
Vanegas
Valentina
V
Quiroz
Yasmir
Y
Mezzano
Sergio
S
Vaziri
Nosratola D
ND
D000804:Angiotensin II / Q000032:analysis; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000032:analysis; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013859:Thiocarbamates / Q000627:therapeutic use*
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016328:NF-kappa B; D013859:Thiocarbamates; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; C066229:prolinedithiocarbamate; D011392:Proline