Shiga Toxin 1 Causes Direct Renal Injury in Rats

Abstract

Infection with Shiga toxin (Stx)-producing Escherichia coli has been implicated to cause hemolytic uremic syndrome, which is characterized by histological abnormalities such as microvascular thrombi and tubular cell damage in the kidney. Although Stx is known to be the major virulence factor of the pathogen, it is still unclear whether Stx directly impairs renal cells in vivo to cause such histological changes and deterioration of renal function. To assess the consequence of the direct action of Stx on renal cells, left kidneys of rats were perfused with Stx1 from the renal artery through the renal vein and then revascularized. Kidneys of control animals were perfused with the vehicle alone. On day 1, apoptosis and induction of tumor necrosis factor alpha gene expression were noticed to occur in the medulla of the Stx1-perfused kidneys. On day 3, extensive tubular injuries were observed by light microscopy: aggregated platelets and monocytic infiltrates in both glomeruli and the medullary interstitium were detected by immunostaining. Tubular changes were more extensive on day 9, with areas of infarction seen in the cortex and medulla. These changes were not found to occur in the sham-operated kidneys. No obvious glomerular changes were detected by light microscopy at any time point. When nonperfused right kidneys were removed after the Stx1 perfusion of the left kidneys, the serum creatinine and blood urea nitrogen levels were increased from day 2, and acute renal failure followed on day 3. These results indicate that Stx1 caused glomerular platelet aggregation, tubular damage, and acute deterioration of renal function by acting directly on renal cells.

Pathologic Changes in Mice Induced by Subtilase Cytotoxin, a Potent NewEscherichia coliAB5Toxin That Targets the Endoplasmic Reticulum

“…Stx [13][14][15]. Hematologically, there was evidence of microangiopathic hemolytic anemia, thrombocytopenia, and leukocytosis.…”

Monocyte Chemoattractant Protein 1, Macrophage Inflammatory Protein 1α, and RANTES Recruit Macrophages to the Kidney in a Mouse Model of Hemolytic-Uremic Syndrome

“…It is not surprising that these chemokines are produced by tubular epithelial cells, considering previous studies documenting the ability of these cells to produce various cytokines and chemokines, including MCP-1, RANTES, and MIP-1␣ (1,37). Additionally, renal tubular cells have been shown to be a primary target of Stx in animal models and in cell culture, inducing both apoptosis and cytokine secretion (8,12,19,34,35).…”

Treatment options for HUS secondary to Escherichia coli O157:H7

“…14,23 However, a direct effect of Stx on vascular endothelial, mesangial and tubular epithelial cells has been postulated considering their microanatomical position and exquisite sensitivity to Stx in vitro. [24][25][26] Extrarenal manifestations Many STEC-infected children exhibit subtle systemic manifestations, such as fever, CNS symptoms (irritability, seizures, lethargy), hyponatremia, transient subtle decrease of circulating platelets, and urine abnormalities. 9,27 Clinically severe (15-25%) or devastating complications are infrequent and predominantly associated with HUS.…”