Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride

We have previously shown that in renal cortex, COX-2 expression is localize d to macula densa and surrounding cortical thick ascending limb of Henle (c TALH). Dietary salt restriction increases local expression of COX-2, which mediates renin production and secretion. Given that decreased luminal chlor ide [Cl-] at the level of the macula densa increases renin production and s ecretion, we investigated the role of extracellular ion concentration on CO X-2 expression. Quiescent rabbit cTALH cells were incubated in a physiologi cal salt solution containing high or low levels of NaCl. Immunoreactive COX -2 expression increased significantly in the low NaCl solution. COX-2 expre ssion also increased after administration of the Na+/K+/2Cl(-) cotransport inhibitor, bumetanide. Selective substitution of chloride led to increased COX-2 expression, whereas selective substitution of sodium had no effect. T he p38 MAP kinase inhibitor PD169316 decreased low NaCl-induced COX-2 expre ssion. Low-salt or low-chloride medium induced cultured cTALH to accumulate greater than or equal to 3-fold higher levels of pp38, the activated (phos phorylated) form of p38; low-salt medium also increased pJNK and pERK level s. Feeding rats a low-salt diet for 14 days induced a significant increase in renal cortical pp38 expression, predominantly in the macula densa and cT ALH. These results suggest that reduced extracellular chloride leads to inc reased COX-2 expression, which may be mediated by activation of a p38-depen dent signaling pathway.