AGE-RELATED ALTERATIONS OF 1,25(OH)2-VITAMIN D3 –DEPENDENT P38 MAPK ACTIVATION

VERONICA GONZALEZ PARDO; ANA RUSSO DE BOLAND

Pinanar, Bs As, Argentina

Congreso; XLI REUNION ANUAL DE SAIB; 2005

SAIB

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. We have previously shown that the hormone activates the  mitogen-activated protein kinases ERK1/2 and p38 MAPK in rat intestinal cells (enterocytes). In the present study, we analyzed, 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, the tyrosine phosphorylation and activity of p38 MAPK, with a maximun at 3 min (+2 fold). Basal levels of p38 MAPK tyrosine-phosphorylation were not significantly changed in old enterocytes, but the hormone response was greatly diminished (+1 fold at 2-3 min). p38 MAPK phosphorylation impairment in old animals was not related to significant changes of the kinase protein expression and do not explain the decreased response to 1a,25(OH)2D3. Extracellular Ca2+ chelation with EGTA, suppressed hormone activation of p38 MAPK in both, young and aged rats, demonstrating that extracellular Ca2+ is required for full activation of p38 MAPK in enterocytes stimulated with 1a,25(OH)2D3. Enterocytes exposure to the hormone also resulted in the rapid induction of c-Fos expression, peaking at 5 min (+3 fold), effect that was blocked by SB 203580, a specific inhibitor of p38 MAPK, and partially suppressed by the ERK1/2 inhibitor PD 98059. 1a,25(OH)2D3-induced c-Fos expression is lost in old animals. Impairment of 1a,25(OH)2D3  activation of p38 MAPK upon ageing results in abnormal hormone regulation of  the c-Fos oncoprotein synthesis and thereby may affect intestinal cell function.