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Effect of morphine on renomedullary interstitial cell proliferation and matrix accumulation
P C Singhal1, P Sharma, N Gibbons
1Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, N.Y. 11040, USA.
Abstract:
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.
Insights
Morphine, a heroin metabolite, stimulates renal interstitial cell proliferation and collagen production, contributing to kidney scarring in heroin users. This effect is mediated by IL-6 and protein kinase C.
Area of Science:
- Nephrology
- Pharmacology
- Cell Biology
Background:
- Renal interstitial scarring is a key characteristic of heroin-associated nephropathy.
- Morphine is an active metabolite of heroin with potential renal effects.
Purpose of the Study:
- To investigate the effects of morphine on rat renal medullary interstitial cell (RMIC) proliferation and matrix accumulation.
- To explore the role of morphine in the pathogenesis of renal interstitial pathology.
Main Methods:
- Cultured rat RMICs were treated with varying concentrations of morphine.
- Cell proliferation was assessed using [3H]thymidine and bromodeoxyuridine incorporation.
- mRNA expression for c-jun and c-myc was analyzed.
- Collagen type I and III, laminin, and fibronectin accumulation were quantified.
- Interleukin-6 (IL-6) and protein kinase C (PKC) pathways were investigated using neutralizing antibodies and inhibitors.
Main Results:
- Morphine significantly enhanced RMIC proliferation in a dose- and time-dependent manner.
- Morphine increased mRNA expression of c-jun and c-myc in RMICs.
- Morphine dose-dependently increased collagen type I and III accumulation.
- Nalbuphine did not affect RMIC proliferation.
- Inhibition of IL-6 or PKC attenuated morphine-induced RMIC proliferation.
Conclusions:
- Morphine promotes RMIC proliferation and extracellular matrix accumulation, suggesting a role in heroin-associated nephropathy.
- The findings support a hypothesis that morphine contributes to renal interstitial pathology in heroin addiction.
- Targeting IL-6 or PKC pathways may offer therapeutic potential for managing morphine-induced kidney damage.