TY - JOUR
T1 - Netrin-1 regulates colon-kidney cross talk through suppression of IL-6 function in a mouse model of DSS-colitis
AU - Ranganathan, Punithavathi
AU - Jayakumar, Calpurnia
AU - Santhakumar, Manicassamy
AU - Ramesh, Ganesan
PY - 2013
Y1 - 2013
N2 - 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 overexpres-sion of netrin-1 suppressed both colitis and colitis-induced acute kidney injury, which was associated with reduced weight loss, neu-trophil 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.
AB - 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 overexpres-sion of netrin-1 suppressed both colitis and colitis-induced acute kidney injury, which was associated with reduced weight loss, neu-trophil 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.
KW - Acute kidney injury
KW - Colitis
KW - IL-6
KW - Netrin-1
KW - Organ cross talk
UR - http://www.scopus.com/inward/record.url?scp=84878558748&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878558748&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00702.2012
DO - 10.1152/ajprenal.00702.2012
M3 - Article
C2 - 23445618
AN - SCOPUS:84878558748
SN - 0363-6127
VL - 304
SP - F1187-F1197
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 9
ER -