Submitted on August 16, 2007
Accepted on March 26, 2008
Morphine Induces Mesangial Proliferation and Glomerulopathy via Kappa Opioid Receptors
Marc L. Weber1, Mariya Farooqui2, Julia Nguyen3, Michael A. Ansonoff4, John E Pintar5, Robert P. Hebbel6, and Kalpna Gupta2*
1 Medicine-Renal, University of Minnesota, Minneapolis, Minnesota, United States
2 Medicine-Heme/Onc/Transplant, University of Minnesota, Minneapolis, Minnesota, United States
3 Heme/Onc/Transplant, University of Minnesota, Minneapolis, Minnesota, United States
4 Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, United States
5 Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, United States
6 University of Minnesota; Medicine-Heme/Onc/Transplant, University of Minnesota, Minneapolis, Minnesota, United States
* To whom correspondence should be addressed. E-mail: gupta014{at}umn.edu.
Morphine sulfate (MS) stimulates mesangial cell (MC) proliferation, a process central to development of glomerular disease. The purpose of this study was to examine if 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 weeks 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 in vivo. 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 mesangial cell proliferation, we further examined the OR-specific effects of MS in mesangial cells 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.
