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.