AGEING AFFECTS P38 MAPK SIGNALING DEPENDENT ON 1a,25(OH)2-VITAMIN D3 IN RAT ENTEROCYTES

VERONICA GONZALEZ PARDO; RICARDO BOLAND; ANA RUSSO DE BOLAND

Victoria BC, Canadá

Workshop; 13 th WORKSHOP ON VITAMIN D; 2006

In intestinal cells, 1a,25(OH)2-vitamin D3 (1a,25(OH)2D3) regulates gene expression via the specific intracellular vitamin D receptor and induces fast non-transcriptional responses involving stimulation of transmembrane signal transduction pathways. In the present study, we analysed, for the first time, alterations in p38 MAPK response to 1a,25(OH)2D3 in rat enterocytes with ageing. In enterocytes from young rats, the hormone increased, in a time- and dose-dependent fashion, tyrosine phosphorylation of p38 MAPK, peaking at 3 min (+2-fold). Basal levels of p38 MAPK tyrosine-phosphorylation were lower in old enterocytes and the hormone response was greatly diminished (+0.5-fold at 3 min). Ca2+ chelation or c-Src pharmacological inhibition suppressed hormone activation of p38 MAPK in both, young and aged rats. Two other vitamin D3 metabolites, 25OHD3 and 24,25(OH)2D3 also enhanced p38 MAPK phosphorylation, and  to a similar extent than 1a,25(OH)2D3, ability that is lost in old animals. p38 MAPK phosphorylation impairment with ageing was not related to significant changes of the kinase protein expression and do not explain the decreased response to 1a,25(OH)2D3. Of interest, we found that VDR protein level and specific binding to subcellular fractions was diminished in aged rats. Enterocyte exposure to the hormone also resulted in the rapid induction of c-Fos expression, peaking at 5 min (+3-fold), effect that was not observed in old animals. Impairment of 1a,25(OH)2D3 activation of p38 MAPK upon ageing may result in abnormal hormone regulation of  the c-Fos oncoprotein synthesis and thereby may affect intestinal cell function.