Title: Activation of guanylate cyclase C signaling pathway protects intestinal epithelial cells from acute radiation-induced apoptosis.

Authors: Garin-Laflam, M P; Steinbrecher, K A; Rudolph, J A; Mao, J; Cohen, M B

Published In Am J Physiol Gastrointest Liver Physiol, (2009 Apr)

Abstract: Uroguanylin (UGN) is a peptide hormone that binds to and activates the intestinal epithelial cell (IEC) transmembrane receptor guanylate cyclase C (GC-C), which in turn increases intracellular cGMP. Gene targeting of murine UGN or GC-C results in significantly lower levels of cGMP in IECs. On the basis of effects of cGMP in nonintestinal systems, we hypothesized that loss of GC-C activation would increase intestinal epithelial apoptosis following radiation-induced injury. We first compared apoptosis from the proximal jejunum of C57BL/6 wild-type (WT) and GC-C knockout (KO) mice 3 h after they received 5 Gy of gamma-irradiation. We then investigated whether supplementation via intraperitoneal injection of 1 mM 8BrcGMP would mitigate radiation-induced apoptosis in these experimental animals. Identical experiments were performed in BALB/c UGN WT and KO mice. Apoptosis was assessed by quantitating morphological indications of cell death, terminal dUTP nick-end labeling, and cleaved caspase 3 immunohistochemistry. Both UGN KO and GC-C KO mice were more susceptible than their WT littermates in this in vivo model of apoptotic injury. Furthermore, cGMP supplementation in both GC-C and UGN KO animals ameliorated radiation-induced apoptosis. Neither WT strain demonstrated significant alteration in apoptotic susceptibility as a result of cGMP supplementation before radiation injury. These in vivo findings demonstrate increased radiosensitivity of IECs in UGN and GC-C KO mice and a role for cGMP as a primary downstream mediator of GC-C activation in the protection of these IECs from radiation-induced apoptosis.

PubMed ID: 19221018

MeSH Terms: Animals; Apoptosis/radiation effects; Cyclic GMP/metabolism; Epithelial Cells/drug effects*; Epithelial Cells/radiation effects*; Female; Gamma Rays/adverse effects; Guanylate Cyclase/genetics; Guanylate Cyclase/metabolism*; Immunohistochemistry; In Situ Nick-End Labeling; Intestinal Mucosa/cytology*; Intestinal Mucosa/drug effects; Intestinal Mucosa/radiation effects; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Natriuretic Peptides/genetics; Natriuretic Peptides/metabolism; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide/genetics; Receptors, Peptide/metabolism*; Signal Transduction/physiology*; Specific Pathogen-Free Organisms