endothelin-1 and Hemolytic-Uremic-Syndrome

Escherichia coli-derived verotoxins (VTs) play a critical role in the pathogenesis of hemolytic uremic syndrome (HUS) in major part due to vascular endothelial damage. Perturbations in endothelial phenotype account for many of the clinical features observed in patients. VTs inactivate host cell ribosomes and prevent protein synthesis. Interestingly, however, they also dramatically alter gene expression at concentrations that have only minor effects on overall mRNA translation. Using endothelin-1 as a model, we describe the molecular mechanisms by which VT alters the endothelial cell phenotype in HUS. RNA metabolism pathways and effects on translation may play central roles in the molecular events operative in vascular injury mediated by these potent bacteria-derived exotoxins.

Topics: Animals; Endothelin-1; Endothelium, Vascular; Hemolytic-Uremic Syndrome; Humans; Phenotype; Polyribosomes; RNA Stability; RNA, Messenger; Shiga Toxins; Shiga-Toxigenic Escherichia coli; Up-Regulation

The objective of the study was to investigate the role of endothelin-1 in the pathogenesis of scleroderma renal crisis in patients with systemic sclerosis. We used immunohistochemical analysis with anti-endothelin-1 and anti-von Willebrand factor antibodies in comparing kidney biopsies from patients with systemic sclerosis and scleroderma renal crisis (n = 14); from normal kidneys (n = 5); and from patients with typical hemolytic uremic syndrome and thrombotic microangiopathy (n = 5), antiphospholipid syndrome (n = 6), diabetic nephropathy (n = 5), minimal change disease with cyclosporine toxicity (n = 5), or nephroangiosclerosis (n = 5). Kidney biopsies from all systemic sclerosis patients presented specific lesions: glomerular lesions with thickened capillary walls (n = 6, 42.8%), mesangiolysis (n = 3, 21.4%), fibrin thrombi (n = 3, 21.4%), hypertrophy of juxtaglomerular apparatus (n = 5, 35.7%), arteriolar lesions showing mucinous intimal thickening and lumen mucoid occlusions (n = 13, 92.8%), proliferation of intimal cells (ie, "onion-skin" lesions; n = 13, 92.8%), fibrinoid necrosis (n = 3, 21.4%), and fibrin thrombosis (n = 4, 28.6%). Chronic lesions in large arteries showed modifications such as fibrous intimal thickening (n = 13, 92.8%). The pattern of endothelial staining for endothelin-1 in both glomeruli and arteriolar lesions appears to be specific for scleroderma renal crisis. Glomerular endothelin-1 staining without arteriolar staining was seen in hemolytic uremic syndrome; and isolated arteriolar staining (without glomerular staining) was seen in a number of conditions including antiphospholipid nephropathy, cyclosporine toxicity, and diabetic nephropathy. Endothelin-1 is overexpressed in glomeruli and arterioles of patients with scleroderma renal crisis, which suggests that endothelin-1 might be a therapeutic target in this condition.

Topics: Acute Kidney Injury; Adult; Aged; Antiphospholipid Syndrome; Endothelin-1; Female; Hemolytic-Uremic Syndrome; Humans; Kidney; Male; Middle Aged; Scleroderma, Systemic; von Willebrand Factor

Shiga toxin, produced by Escherichia coli O157:H7, is important for the pathogenicity of the epidemic form of hemolytic uremic syndrome (HUS). This toxin has recently been found to stimulate endothelin-1 synthesis in cultured endothelial cells in vitro.. We investigated endothelin and cytokine levels in sera during a large outbreak of E. coli O157:H7 infection in Osaka, Japan, in 1996. Eleven patients with HUS and 9 patients with hemorrhagic colitis at the onset of E. coli O157:H7 infection were studied.. Serum IL-6 (p < 0.01), IL-8 (p < 0.05), IL-10 (p < 0.001) and endothelin (p < 0.001) levels were significantly increased in patients with HUS compared to those with colitis only. The serum thrombomodulin level, a molecular marker of endothelial damage, also showed a significant positive correlation with serum IL-6 (p < 0.01), IL-8 (p < 0.01), IL-10 (p < 0.01) and endothelin (p < 0.001) levels. In a HUS patient, the increase in serum IL-10 and endothelin levels reached a plateau prior to the peak of serum creatinine levels.. Increased serum endothelin synthesis by Shiga toxin in vivo was proven in HUS secondary to E. coli O157:H7 infection. Increased serum endothelin and IL-10 levels were speculated to be associated with the development of HUS through vascular endothelial damage caused by E. coli O157:H7 infection.

Topics: Case-Control Studies; Colitis; Creatinine; Disease Outbreaks; Endothelin-1; Escherichia coli Infections; Escherichia coli O157; Female; Gastrointestinal Hemorrhage; Hemolytic-Uremic Syndrome; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Japan; Male; Thrombomodulin; Time Factors

Interaction of bipartite Escherichia coli O157-derived verotoxins (VTs) 1 and 2 (Shiga toxin 1 and 2) with vascular endothelium is believed to play a central role in the pathogenesis of the thrombotic microangiopathy and ischemic lesions characteristic of hemolytic uremic syndrome and of E. coli O157-associated hemorrhagic colitis. We defined the effects of VTs on the expression of potent endothelial cell-derived regulators of vascular wall function, namely endothelin-1 (ET-1) and nitric oxide (NO). In quiescent bovine aortic endothelial cells, both VT1 and VT2, but not receptor-binding VT B-subunit which lacks N-glycosidase activity, induced concentration-dependent (0.1-10 nM) increases in steady state preproET-1 mRNA transcript levels, an effect that was maximal at 12-24 h. Metabolic-labeling experiments indicated that VTs increased preproET-1 mRNA transcript levels at concentrations that had trivial effects on nascent DNA, RNA, and protein synthesis. In contrast to preproET-1, endothelin converting enzyme-1 and endothelial constitutive NO synthase mRNA transcript levels remained unchanged. Consistent with these findings, VTs failed to modulate immunoreactive endothelial constitutive NO synthase expression and basal and calcium-dependent L-[14C]arginine to L-[14C]citrulline conversion or the NO chemiluminescence signal. The plant-derived toxin ricin, which shows a similar molecular mechanism of enzymatic ribosomal modification to VTs, caused comparable effects on these endothelial vasomediators and metabolite incorporation, at 3 log orders lower concentrations. Nuclear transcription and actinomycin D chase experiments indicated that VTs stabilize labile preproET-1 mRNA transcripts in endothelial cells. Therefore, VTs potently increase select mRNA transcript levels in endothelial cells at concentrations of toxins that have minimal effects on protein synthesis. Perturbed expression of endothelial-derived vasomediators may play a pathophysiologic role in the microvascular dysfunction that is the hallmark of hemolytic uremic syndrome and hemorrhagic colitis.

Topics: Animals; Aspartic Acid Endopeptidases; Bacterial Toxins; Cattle; Cells, Cultured; Dactinomycin; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Gene Expression; Hemolytic-Uremic Syndrome; Metalloendopeptidases; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Precursors; Ricin; RNA, Messenger; Shiga Toxin 1; Shiga Toxin 2