Effect of morphine on renomedullary interstitial cell proliferation and matrix accumulation.
Renal interstitial scarring is an important feature of heroin-associated nephropathy. We studied the effect of morphine, an active metabolite of heroin, on cultured rat renal medullary interstitial cell (RMIC) proliferation and matrix accumulation. Morphine (10(-12) M) enhanced (p < 0.001) the proliferation of RMIC (control, 15.0+/-0.5 vs. morphine, 20.4+/-1.1 x 10(4) cells/ml). This effect of morphine was dose and time dependent. [3H]thymidine and bromodeoxyuridine incorporation studies confirmed the mitogenic effect of morphine on RMIC. Morphine also enhanced mRNA expression for c-jun and c-myc on RMIC. However, nalbuphine, a non-addicting alkaloid did not modulate the proliferation of RMIC. Morphine enhanced the accumulation of collagen type I in a dose-dependent manner and also increased (p < 0.001) the accumulation of collagen type III at a high concentration (control, 1,291+/-55.8 vs. morphine, 10(-4) M, 2,697.6+/-257.8 ng/microg protein). Morphine did not modulate the accumulation of laminin or fibronectin. Neutralizing antibody to IL-6 inhibited the effect of morphine on RMIC. H7, a protein kinase C inhibitor, also attenuated the morphine-induced RMIC proliferation. The present study provides a basis for a hypothesis that morphine may be playing a role in the development of renal interstitial pathology in patients with heroin addiction.
Singhal
P C
PC
Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, N.Y. 11040, USA.
Sharma
P
P
Gibbons
N
N
Franki
N
N
Kapasi
A
A
Wagner
J D
JD
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D007679:Kidney Medulla / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D000963:Antimetabolites; D004791:Enzyme Inhibitors; D009294:Narcotics; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D012313:RNA; D009020:Morphine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003094:Collagen; D011493:Protein Kinase C; D001973:Bromodeoxyuridine