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Kidney Int. 2000 Jun;57(6):2319-33.

Glucocorticoid modulates Na+/H+ exchange activity in vascular smooth muscle cells by nongenomic and genomic mechanisms.

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Departments of Nephrology and Endocrinology and Metabolism, Jichi Medical School, Tochigi, Japan.



In vascular smooth muscle cells (VSMCs), Na+/H+ exchange (NHE) plays an important role in intracellular pH (pHi) regulation. The genomic effect of glucocorticoid (GC) on NHE activity has been suggested in VSMCs. However, the nongenomic and genomic effects of GC on NHE activity and the underlying intracellular signaling mechanisms have not yet been demonstrated in VSMCs. Also, it is not known whether there are specific surface-binding sites of GC to the plasma membrane of VSMCs.


The effects of short (3 h)- and long (24 h)-term exposure to corticosterone (CORTI) on NHE activity were studied in cultured rat aortic VSMCs by using pHi measurement with the pH-sensitive fluorescent dye 2'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. The NHE activity was calculated from the initial rate of Na+-dependent pHi recovery after the acid load.


Short-term exposure of VSMCs to CORTI (10-6 mol/L) increased NHE activity, whereas long-term exposure to CORTI decreased it. The inhibitors of gene transcription (actinomycin D) and of protein synthesis (cycloheximide) did not affect the short-term effect of CORTI on NHE activity, but inhibited the long-term effect of CORTI on NHE activity. The cytosolic GC receptor (GR) antagonist (RU38486) inhibited both the short- and long-term effects of CORTI on NHE activity, but the cytosolic mineralocorticoid receptor antagonist (spironolactone) did not influence either the short- or long-term CORTI effects. Two protein kinase C (PKC) inhibitors (staurosporine A and calphostin C) and PKC down-regulation [24-h pre-exposure to phorbol 12-myristate 13-acetate (PMA)] inhibited both short- and long-term CORTI effects. Exposure to PMA for three hours mimicked the short-term CORTI effect. The short-term CORTI effect was inhibited by the disruptor of microtubule (colchicine), but not by the disruptor of filamentous-actin (cytochalasin B). The long-term exposure to CORTI decreased NHE (NHE-1) mRNA levels to 0.65 times the control level, whereas the short-term exposure to CORTI caused no effect. Scatchard analysis of [3H]CORTI surface binding to VSMCs showed a single class of CORTI binding sites with a Bmax of 876.2 fmol per mg of cell protein and a Kd of 12.2 nmol/L. RU38486 also inhibited [3H]CORTI surface binding to VSMCs.


In VSMCs, NHE activity is stimulated by short-term exposure to CORTI, but is inhibited by long-term exposure to CORTI. The short-term stimulatory effect of CORTI on NHE activity is independent of gene transcription and protein synthesis, is mediated through the CORTI surface receptor, and occurs through a microtubule-dependent process. The long-term inhibitory effect of CORTI on NHE activity requires gene transcription and protein synthesis and occurs only through the cytosolic GR. The short- and long-term effects of CORTI on NHE activity occur via PKC activation. Therefore, CORTI differentially modulates NHE activity in VSMCs by nongenomic and genomic mechanisms.

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