Activation of extracellular signal-regulated kinase mediates apoptosis induced by uropathogenic Escherichia coli toxins via nitric oxide synthase: protective role of heme oxygenase-1.
Pyelonephritis is a risk factor for renal tubular epithelial cell damage in children. The inter- and intracellular regulator nitric oxide (NO) plays a role in the modulation of cellular viability in urinary tract infections, but the role of the NO pathway in renal proximal tubular-cell death remains unclear. The present study demonstrates that, in renal epithelial cells undergoing death mediated by Escherichia coli strain ARD6 serotype O6K13H1 (O6), levels of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and inducible NO synthase (iNOS) proteins are up-regulated, but levels of endothelial NO synthase are down-regulated. When NO synthase (NOS) activity is inhibited by the specific inhibitor of NOS or mitogen-activated protein kinase kinase, cells are prevented from death. Moreover, down-regulating protein 53 (p53) does not prevent the cells from dying, although p53 is up-regulated in O6-exposed cells. Up-regulation of heme oxygenase (HO)-1 by sodium nitroprusside or by the specific activator hemin inhibits cell death. In conclusion, the activation of ERK mediates O6 toxin-mediated renal cell death via induction of iNOS. Stimulation of HO-1 protects cells against death.
Chen
Ming
M
Department of Pediatrics, Pediatric Nephrology Unit, Karolinska University Hospital-Huddinge, Stockholm, Sweden. ming.chen@klinvet.ki.se
Bao
Wenjie
W
Aizman
Roman
R
Huang
Ping
P
Aspevall
Olle
O
Gustafsson
Lars E
LE
Ceccatelli
Sandra
S
Celsi
Gianni
G
D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000633:toxicity*; D002478:Cells, Cultured; D015536:Down-Regulation; D004926:Escherichia coli / Q000472:pathogenicity*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D007687:Kidney Tubules, Proximal; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011704:Pyelonephritis / Q000382:microbiology; D013552:Swine; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D001427:Bacterial Toxins; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases