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Long term effects of morphine on mesangial cell proliferation and matrix synthesis

1992; Elsevier BV; Volume: 41; Issue: 6 Linguagem: Inglês

10.1038/ki.1992.226

1523-1755

Pravin C. Singhal, Nora Gibbons, Mirel Abramovici,

Berberine and alkaloids research

Long term effects of morphine on mesangial cell proliferation and matrix synthesis.Since focal glomeruloscierosis is the predominant glomerular lesion in heroin nephropathy and since mesangial expansion is considered to be a precursor of giomeruloscierosis, we have evaluated the effect of opiates on mesangial cell (MC) proliferation and matrix synthesis.We showed, using a fluorometric assay, that MC are not capable of metabolizing heroin to its active metabolite morphine.Cells exposed to morphine (l0 M or i0 M) in prolonged cultures either continuously (Group A) or intermittently (Group B) showed enhanced incorporation of [3H]thymidine when compared to control cells (control, 88600 26303 cpm/well vs. morphine iO M -Group A, 321203 52867, P < 0.001; control vs. morphine iO-54-Group B, 223126 46866 cpmlwell, P < 0.01; control, 107593 42284 cpm/well vs. morphine 10 M -Group A, 267108 41866 cpm/well, P < 0.001; control vs. morphine lO-M -Group B, 202317 24325 cpm/well, P < 0,05).However, MC incubated with a lower concentration of morphine (lO_6 M) enhanced DNA synthesis when exposed intermittently only (control, 107593 42284 cpm/well vs. Group B, 219164 15552 cpmlwell, P < 0.05).This growth stimulating effect of morphine (106 M and iO-M) was also observed at earlier time points, that is, one-and one-and-a-half-week old cultures.However, in one-week-old cultures, morphine in a higher concentration (l0 M) showed a suppressive effect (P < 0.05) on MC proliferation (morphine, 3620 220 cpm/well vs. control, 4668 410 cpmlwell).This effect not only subsided by one and a half weeks but morphine (10-a M) treated cells enhanced MC proliferation.An opioid antagonist, naloxone attenuated the effect of morphine in one and half week old cultures.Morphine at 10 M to l0 M concentrations enhanced incorporation of ['H]proline in the extracellular proline pool (a component of mesangial matrix) when compared to control (control, 309661 3992 vs. morphine iO M, 363104 10539 cpm/well, P < 0.05 or morphine l0 M, 397954 31008 cpm/well, P < 0.001 or morphine 10 M, 384630 26369 cpm/well, P < 0.01).In addition, MC incubated with morphine (l06 si and IO 54) also enhanced (P < 0.001) synthesis of laminin.MC incubated with morphine (iO M or io, 12 weeks) had a greater number of hillocks (foci of cell proliferation and aggregated matrix) when compared with untreated cells.Morphine treated MC synthesized a decreased amount of PGE2 (129 48 pg/mg protein, P < 0.02) when compared to POE2 production by untreated cells ( 493123 pg/mg protein).Morphine pretreated MC when stimulated with arginine vasopressin (AVP, 10-6 M) also produced a lesser amount of PGE2 (214 51 pg/mg protein, P < 0.05) when compared to PGE2 production by control cells under stimulation with AVP (1393 451 pg/mg protein).Our results suggest that morphine may be playing a direct role in mesangial expansion in opiate addicts.