Shock-induced stress induces loss of microvascular endothelial Tie2 in the kidney which is not associated with reduced glomerular barrier function

Abstract

Both hemorrhagic shock and endotoxemia induce a pronounced vascular activation in the kidney which coincides with albuminuria and glomerular barrier dysfunction. We hypothesized that changes in Tie2, a vascular restricted receptor tyrosine kinase shown to control microvascular integrity and endothelial inflammation, underlie this loss of glomerular barrier function. In healthy murine and human kidney, Tie2 is heterogeneously expressed in all microvascular beds, although to different extents. In mice subjected to hemorrhagic and septic shock, Tie2 mRNA and protein were rapidly, and temporarily, lost from the renal microvasculature, and normalized within 24 h after initiation of the shock insult. The loss of Tie2 protein could not be attributed to shedding as both in mice and healthy volunteers subjected to endotoxemia, sTie2 levels in the systemic circulation did not change. In an attempt to identify the molecular control of Tie2, we activated glomerular endothelial cell cultures and human kidney slices in vitro with LPS or TNF-alpha, but did not observe a change in Tie2 mRNA levels. In parallel to the loss of Tie2 in vivo, an overt influx of neutrophils in the glomerular compartment, which coincided with proteinuria, was seen. As neutrophil-endothelial cell interactions may play a role in endothelial adaptation to shock, and these effects cannot be mimicked in vitro, we depleted neutrophils before shock induction. While this neutrophil depletion abolished proteinuria, Tie2 was not rescued, implying that Tie2 may not be a major factor controlling maintenance of the glomerular filtration barrier in this model.

The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice

“…explain the nephrin deficiency via an indirect pathway (i.e., loss of synaptopodin), as shown in other albuminuric model (19). Bacterial wall components-such as LPS and histone-related proteins-are known to elicit proteinuria (1,32,33,35). These studies provide a clue to explain albuminuria occurred in septic patients (6,25,28), or in subjects after Streptococcal infection in children (13), but the molecular basis has not been fully understood.…”

“…However, little information is available about the nephrin dynamism during sepsis-induced albuminuria. It is demonstrated that LPS elicits "transient" albuminuria in rodents (1,27,32). However, the mechanisms of reversibility have not been fully elucidated yet.…”

“…LPS is known to elicit albuminuria in mice (27,32), and this change is recovered within a few days (1). To confirm the reversibility of albuminuria, we checked the natural course of urinary albumin excretion.…”

“…Furthermore, albuminuria is also a common event during septic diseases (6,25,28), along with inflammatory responses. For example, lipopolysaccharide (LPS) of Escherichia coli, or histone-like protein of Streptococcal pyogenesis, often triggers albuminuria and glomerular nephritis (1,32,33), and this is associated with over-production of pro-inflammatory cytokines by activated macrophages (10,22). However, it is still unclear how sepsis-induced albuminuria is linked with an increase in pro-inflammatory cytokines (i.e., cytokine storm).…”

Targeted siRNA delivery to diseased microvascular endothelial cells—Cellular and molecular concepts

“…It should be noted, however, that many of these proteins are not homogeneously expressed by the endothelium but rather are (micro)vascular bed specific. Moreover, the kinetics of disease-induced target epitope expression may spatiotemporally differ between endothelial cell subsets in the diseased sites (13). This could have either an advantageous or a detrimental effect with regard to specificity and/or extent of local accumulation of the drug delivery formulation.…”