ISSN:
0021-9541
Keywords:
Life and Medical Sciences
;
Cell & Developmental Biology
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Biology
,
Medicine
Notes:
The present study examined responses of cultured rat glomerular mesangial cells to exogenous exposure of epoxyeicosatrienoic acids (EET's), products of cytochrome P450 epoxygenase. One day after administration of 8, 9- or 14, 15-EET, cultured rat mesangial cells demonstrated significant increases in [3H]thymidine incorporation (10-7 M 14, 15-EET: 120 ± 7% of control; n = 6; P 〈 0.025; 10-6 M 14, 15-EET: 145 ± 10%; n = 20; P 〈 0.0005; 10-6 M 8,9-EET: 167 ± 31%; n = 9; P 〈 0.05), which was not affected by addition of the cyclooxygenase inhibitor indon ethacin. In addition to stimulation of [3H]thymidine incorporation, the epoxides stimulated mesangial cell proliferation. 14, 15-EET administration induced intracellular alkalinization of 0.2-0.3 pH units, which was prevented by extracellular Na+ removal and blunted by amiloride (0.5 mM). Following intracellular acidification with NH4Cl addition and removal, 〉 85% of 3 mM 22Na uptake into mesangial cells was inhibited by I mM amiloride, indicating Na+ /H+ exchange. Under these conditions, 14, 15-EET stimulated Na+ /H+ exchange by 42% and 8, 9-EET stimulated Na+ /H+ exchange by 59%. Neither protein kinase C depletion nor addition of the protein kinase C inhibitor, staurosporine, affected this stimulation. In [3H]myo-inositol loaded mesangial cells, no significant stimulation of phosphoinositide hydrolysis was detected in response to administration of 14, 15-EET.Twenty-four hours after addition of [14C] 14, 15-EET, 〉 90% was preferentially esterified to cellular lipids, with predominant incorporation into phosphatidylinositol, phosphatidylethanolamine, and diacylglycerol.Thus, these results demonstrate epoxyeicosatrienoic acids stimulate Na+ /H+ exchange and mitogenesis in mesangial cells. These effects do not appear to be mediated via phospholipase C activation. In addition, 14, 15-EET was selectively incorporated into cellular lipids known to mediate signal transduction. These observations extend the potential biologic roles of c-P450 arachidonate metabolites to include stimulation of cell proliferation and suggest a role for these compounds in vascular and renal injury.
Additional Material:
6 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcp.1041440310
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