Morphine induces mesangial cell proliferation and glomerulopathy via kappa-opioid receptors

Area of Science:

• Nephrology
• Pharmacology
• Molecular Biology

Background:

• Morphine sulfate (MS) is known to stimulate mesangial cell (MC) proliferation, a key factor in glomerular disease development.
• The specific roles of opioid receptors (OR) and STAT3 signaling in MS-induced MC proliferation require elucidation.

Purpose of the Study:

• To investigate the association between specific opioid receptors (OR) and STAT3 signaling pathways and morphine sulfate-induced mesangial cell proliferation.
• To determine the in vivo and in vitro effects of morphine sulfate on kidney structure and mesangial cell activity.

Main Methods:

• Utilized C57Bl/6J and opioid receptor-specific knockout mice treated with morphine sulfate, naloxone, or PBS.
• Analyzed kidney sections for glomerular volume and markers of proliferation (PCNA, Thy1, ED1/CD68).
• Assessed MC proliferation via BrdU ELISA and STAT3 phosphorylation using Western blot in vitro.

Main Results:

• Morphine sulfate induced glomerulopathy and enlarged kidneys, effects reversed by naloxone.
• Glomerular volume increased in mu-OR and delta-OR knockout mice, but not kappa-OR knockout mice, suggesting KOR involvement.
• In vitro, KOR-specific antagonists inhibited MS-induced MC proliferation, while KOR agonists stimulated it.
• MS and KOR agonists induced STAT3 phosphorylation, which was crucial for KOR agonist-induced MC proliferation.

Conclusions:

• Morphine sulfate stimulates glomerulopathy and mesangial cell proliferation primarily through kappa-opioid receptor (KOR) activation.
• STAT3 signaling is a critical downstream mediator of KOR-mediated mesangial cell proliferation.
• Targeting KOR and STAT3 signaling may offer therapeutic strategies for morphine-induced kidney damage.