Long term effects of morphine on mesangial cell proliferation and matrix synthesis.
Since focal glomerulosclerosis is the predominant glomerular lesion in heroin nephropathy and since mesangial expansion is considered to be a precursor of glomerulosclerosis, 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 (10(-5) M or 10(-4) 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 10(-4) M-Group A, 321203 +/- 52867, P less than 0.001; control vs. morphine 10(-4) M-Group B, 223126 +/- 46866 cpm/well, P less than 0.01; control, 107593 +/- 42284 cpm/well vs. morphine 10(-5) M - Group A, 267108 +/- 41866 cpm/well, P less than 0.001; control vs. morphine 10(-5) M - Group B, 202317 +/- 24325 cpm/well, P less than 0.05). However, MC incubated with a lower concentration of morphine (10(-6) M) enhanced DNA synthesis when exposed intermittently only (control, 107593 +/- 42284 cpm/well vs. Group B, 219164 +/- 15552 cpm/well, P less than 0.05). This growth stimulating effect of morphine (10(-6) M and 10(-5) 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 (10(-4) M) showed a suppressive effect (P less than 0.05) on MC proliferation (morphine, 3620 +/- 220 cpm/well vs. control, 4668 +/- 410 cpm/well). This effect not only subsided by one and a half weeks but morphine (10(-4) 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(-6) M to 10(-4) M concentrations enhanced incorporation of [3H]proline in the extracellular proline pool (a component of mesangial matrix) when compared to control (control, 309661 +/- 3992 vs. morphine 10(-4) M, 363104 +/- 10539 cpm/well, P less than 0.05 or morphine 10(-5) M, 397954 +/- 31008 cpm/well, P less than 0.001 or morphine 10(-6) M, 384630 +/- 26369 cpm/well, P less than 0.01). In addition, MC incubated with morphine (10(-6) M and 10(-4) M) also enhanced (P less than 0.001) synthesis of laminin.(ABSTRACT TRUNCATED AT 250 WORDS)
Singhal
P C
PC
Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York.
Gibbons
N
N
Abramovici
M
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced; D007797:Laminin / Q000096:biosynthesis; D008855:Microscopy, Electron, Scanning; D009020:Morphine / Q000633:toxicity*; D009270:Naloxone / Q000494:pharmacology; D011392:Proline / Q000378:metabolism
D007797:Laminin; D009270:Naloxone; D009020:Morphine; D011392:Proline; D015232:Dinoprostone