title: Netrin-1 regulates colon-kidney cross talk through suppression of IL-6 function in a mouse model of DSS-colitis.
abstract: 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.
authors: Dept. of Medicine/Vascular Biology Center, CB-3702, Georgia Regents Univ., 1459 Laney-Walker Blvd., Augusta, GA 30912, USA.
authors: Punithavathi
authors: P
authors: Ranganathan
authors: Calpurnia
authors: C
authors: Jayakumar
authors: Manicassamy
authors: M
authors: Santhakumar
authors: Ganesan
authors: G
authors: Ramesh
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002645:Chickens; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D003106:Colon / Q000503:physiopathology*; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D000075388:Netrin-1; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D015850:Interleukin-6; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D016264:Dextran Sulfate
keywords: IL-6; acute kidney injury; colitis; netrin-1; organ cross talk