Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension.
Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.
Bravo
Yanauri
Y
Instituto Venezolano de Investigaciones Científicas-Zulia, Maracaibo, Venezuela.
Quiroz
Yasmir
Y
Ferrebuz
Atilio
A
Vaziri
Nosratola D
ND
Rodríguez-Iturbe
Bernardo
B
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D006973:Hypertension / Q000139:chemically induced* / Q000150:complications* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007854:Lead / Q000097:blood; D008214:Lymphocytes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000652:urine; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011507:Proteinuria / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
D007166:Immunosuppressive Agents; D051996:Transcription Factor RelA; D013481:Superoxides; D000804:Angiotensin II; D007854:Lead; D008315:Malondialdehyde; D003404:Creatinine; D009173:Mycophenolic Acid