Background. Pain and renal dysfunction occur in sickle cell disease. Morphine used to treat pain also co-activates platelet-derived growth factor receptor-β (PDGFR-β), which can adversely affect renal disease. We examined the influence of morphine in mesangial cells in vitro and in mouse kidneys in vivo. Methods. Mouse mesangial cells treated with 1 μM morphine in vitro or kidneys of transgenic homozygous or hemizygous sickle or control mice (n=3 foreach), treated with morphine (0.75, 1.4, 2.14, 2.8, 3.6, and 4.3 mg kg-1 day-1 in two divided doses during the first, second, third, fourth, fifth, and sixth weeks, respectively), were used. Western blotting, bromylated deoxy uridine incorporation-based cell proliferation assay, reverse transcriptase-polymerase chain reaction, immunofluorescent microscopy, and blood/urine chemistry were used to analyse signalling, cell proliferation, opioid receptor (OP) expression, and renal function. Results. Morphine stimulated phosphorylation of PDGFR-β and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to the same extent as induced by platelet-derived growth factor-BB (PDGF-BB) and promoted a two-fold increase in mesangial cell proliferation. The PDGFR-β inhibitor, AG1296, OP antagonists, and silencing of μ- And κ-OP abrogated morphine-induced MAPK/ERK phosphorylation and proliferation by ∼100%. Morphine treatment of transgenic mice resulted in phosphorylation of PDGFR-β, MAPK/ERK, and signal transducer and activator of transcription 3 (Stat3) in the kidneys. Morphine inhibited micturition and blood urea nitrogen (BUN) clearance and increased BUN and urinary protein in sickle mice. Conclusion. Morphine stimulates mitogenic signalling leading to mesangial cell proliferation and promotes renal dysfunction in sickle mice.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health— National Heart, Lung and Blood Institute grants (grant numbers RO1 HL68802, HL103773 to K.G., PO1 HL55552 to R.P.H.).
- Platelet-derived growth factor
- Sickle cell disease