Abstract
The microvascular endothelium of the kidney glomerulus is injured in Shiga-like toxigenic bacterial infection, genetic or acquired loss of complement regulatory protein function, and allo-immune responses of solid-organ or bone marrow transplantation. Existing models of diseases with glomerular endothelial cell (EC) injury, collectively grouped as thrombotic microangiopathies, are problematic, impeding investigation of the mechanisms of microvascular defense and repair. To develop a model of glomerular endothelial injury in the mouse, we conjugated the M. oreades lectin to the cytotoxin, saporin, (LS) to selectively injure the glomerular endothelium. Injury of the microvasculature was evaluated by light, immunofluorescence, and electron microscopy, and by quantitative RT-PCR of cell-type specific transcripts. Renal function was evaluated by quantitation of serum creatinine. The toxin conjugate induced apoptosis of microvascular ECs in vitro, and subtle histologic features of thrombotic microangiopathy in vivo that were enhanced by co-injection of 50 μg/kg LPS. Among LS/LPS-treated animals, loss of glomerular EC staining correlated with decreased expression of EC-specific transcripts, and impaired kidney function. Selective injury of the glomerular microvasculature with LS toxin conjugate and LPS elicits histologic features of thrombotic microangiopathy and acute kidney failure.
Highlights
The vascular endothelium is the principal target of injury in a group of disorders collectively termed thrombotic microangiopathies (TMA)
To generate a potent compound to selectively injure microvascular endothelial cells, we conjugated the toxin, saporin, to the lectin A derived from M. oreades
Endothelial injury of the kidney glomerular microvasculature is a key feature of diverse diseases resulting in thrombotic microangiopathy
Summary
The vascular endothelium is the principal target of injury in a group of disorders collectively termed thrombotic microangiopathies (TMA). TMA is initiated by diverse processes including uncontrolled complement protein activity caused by inherited or acquired defects in complement regulatory proteins, cytotoxic drugs, or immune responses to allogeneic endothelium in the context of allogeneic bone marrow or solid organ transplantation. The most common cause of TMA is Shiga-toxigenic (Stx) E coli infection. TMA injury occurred in about 25% of infected cases to contribute to the high death rate observed in the recent German epidemic [1,2], and may be associated with chronic renal dysfunction among survivors [3,4]. Transplant-associated TMA is a significant cause of morbidity, mortality, and kidney allograft loss [6,7]
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