Organ cross talk is increasingly appreciated in human disease, and inflammatory mediators are shown to mediate distant organ injury in many disease models.
Colitis and intestinal injury are known to be mediated by infiltrating immune cells and their secreted
cytokines. However, its effect on other organs, such as the kidney, has never been studied. In the current study, we examined the effect of
dextran sulfate sodium (DSS)-
colitis on kidney injury and
inflammation. In addition, we hypothesized that
netrin-1 could modulate colon-kidney cross talk through regulation of
inflammation and apoptosis. Consistent with our hypothesis, DSS-
colitis induced
acute kidney injury in mice. Epithelial-specific overexpression of
netrin-1 suppressed both
colitis and
colitis-induced
acute kidney injury, which was associated with reduced
weight loss, neutrophil infiltration into colon mucosa, intestinal permeability, epithelial cell apoptosis, and
cytokine and
chemokine production in
netrin-1 transgenic mice colon and kidney. To determine whether netrin-1-protective effects were mediated through suppression of
IL-6,
IL-6 knockout mice were treated with DSS and
acute kidney injury was determined.
IL-6 knockout was resistant to
colitis and
acute kidney injury. Moreover, administration of
IL-6 to
netrin-1 transgenic mice did not affect the netrin-1-protective effects on the colon and kidney, suggesting that
netrin-1 may reduce both
IL-6 production and its activity. The present study identifies previously unrecognized cross talk between the colon and kidney, and
netrin-1 may limit distant organ injury by suppressing inflammatory mediators and apoptosis.