title: Morphine induces mesangial cell proliferation and glomerulopathy via kappa-opioid receptors.
abstract: Morphine sulfate (MS) stimulates mesangial cell (MC) proliferation, a process central to development of glomerular disease. The purpose of this study was to examine whether specific opioid receptors (OR) and signal transducer and activators of transcription 3 (STAT3) signaling are associated with MS-induced MC proliferation. C57Bl/6J and OR-specific knockout (KO) mice were treated for up to 6 wk with PBS, MS (0.7-2.14 mg/kg), naloxone (equimolar to MS), or MS+naloxone (n = 6 per group). Glomerular volume and expression of PCNA, Thy1, and ED1/CD68 were analyzed in kidney sections. Cell proliferation and STAT3 phosphorylation were analyzed by bromodeoxyuridine (BrdU) ELISA and Western blot, respectively, in MCs in vitro. MS treatment led to enlarged kidneys and glomerulopathy and naloxone reversed these effects. MS treatment increased glomerular volume in both mu-OR (MOR) KO and delta-OR (DOR) KO mice, but not in kappa-OR (KOR) KO mice. To ascertain that MS-induced glomerulopathy in vivo was due to MC proliferation, we further examined the OR-specific effects of MS in MCs in vitro. MS-induced MC proliferation in vitro was inhibited by KOR-specific nor-BNI, but not by DOR or MOR-specific antagonists naltrindol or CTOP, respectively. KOR-specific agonist U50488H stimulated proliferation of MCs, but DOR-specific agonist DPDPE and MOR-specific agonist DAMGO did not. MS failed to stimulate proliferation of MCs from KOR KO mice. MS and KOR agonists induced STAT3 phosphorylation, and STAT3 inhibitor blocked KOR agonist-induced MC proliferation. We show that MS stimulates glomerulopathy and MC proliferation via KOR and STAT3 signaling.
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Weber
authors.forename: Mariya
authors.initials: M
authors.lastname: Farooqui
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Ansonoff
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: Kalpna
authors.initials: K
authors.lastname: Gupta
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D017473:Receptors, Opioid, kappa; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D009020:Morphine