Role of p38 MAP kinase pathway in a toxin-induced model of hemolytic uremic syndrome.
The role of proinflammatory cytokines in a rat model of toxin-induced hemolytic uremic syndrome (HUS) was studied. Male Sprague-Dawley rats underwent continuous saline infusion (6 ml/h) via a tail vein and received a bolus injection of saline (control), lipopolysaccharide (LPS, 10 microg/100 g body weight), ricin (6.7 microg/100 g body weight), or ricin with LPS (ricin+LPS). They were then observed for 8 h. Blood samples and kidney tissues were obtained at the end of the experiment. The effects of FR 167653, a potent inhibitor of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) production, were also examined in ricin+LPS-treated rats. Only ricin+LPS-treated rats developed significant thrombocytopenia, hemolysis, and oliguric acute renal failure with extensive glomerular thrombotic microangiopathy, which was characterized by glomerular microthrombi and apoptosis of glomerular endothelial cells. Thrombotic microangiopathy was not detected in other organs, including the brain, liver, spleen, pancreas, lung, colon, and intestine. Significantly elevated levels of serum IL-1beta and TNF-alpha were detected only in ricin+LPS-treated rats. Treatment of ricin+LPS-treated rats with FR 167653 significantly reduced the serum levels of IL-1beta and TNF-alpha, accompanied by improvement of the oliguric renal failure and glomerular thrombotic microangiopathy. These findings indicate that the increased serum levels of IL-1beta and TNF-alpha, which probably result in the apoptosis of glomerular endothelial cells, play a pivotal role in the development of this rat model of toxin-induced HUS. The findings also suggest that inhibition of these proinflammatory cytokines may prevent the development of HUS.
Fu
Xue Jun
XJ
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
Iijima
Kazumoto
K
Nozu
Kandai
K
Hamahira
Kiyoshi
K
Tanaka
Ryojiro
R
Oda
Tatsuya
T
Yoshikawa
Norishige
N
Matsuo
Masafumi
M
D000818:Animals; D004195:Disease Models, Animal; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D020935:MAP Kinase Signaling System; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012276:Ricin / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C104334:FR 167653; D008070:Lipopolysaccharides; D011720:Pyrazoles; D011725:Pyridines; D012276:Ricin; D048051:p38 Mitogen-Activated Protein Kinases