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Marc L Weber,1 Derek Vang,2 Paulo E Velho,2,3 Pankaj Gupta,4 John T Crosson,5 Robert P Hebbel,2 Kalpna Gupta21Division of Renal Diseases and Hypertension; 2Vascular Biology Center and Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA; 3Department of Medicine, University of Campinas Medical School, Campinas, SP, Brazil; 4Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota and VA Medical Center, Minneapolis, MN, USA; 5Department of Lab Medicine Pathology, Hennepin County Medical Center, Minneapolis, MN, USAAbstract: Patients with sickle cell disease (SCD) are often treated with opioids for severe pain. Although opioids are known to have renal-specific effects, their role in nephropathy in SCD remains unknown. Because a subset of patients receives opioids for long periods of time, we examined the influence of chronic morphine treatment on mice with pre-existing renal disease expressing varying amounts of sickle hemoglobin. Morphine treatment for 3–6 weeks resulted in a variety of defects in renal morphology observed using light and electron microscopy. Notably, morphine induced glomerular pathology, resulting in increased glomerular volume, mesangial expansion, mesangial cell proliferation, parietal cell metaplasia, podocyte effacement, and microvillus transformation. Cystic tubulopathy and hemeoxygenase-1 expression and activity were also increased in morphine-treated mice. Naloxone, a non-selective opioid receptor (OR) antagonist, ameliorated these effects. Functionally, the urine albumin to creatinine ratio was increased following acute as well as chronic morphine treatment. These results suggest that clinically relevant doses of morphine induce renal pathology and that OR antagonists may be effective for ameliorating morphine-induced renal disease.Keywords: mesangial cell, morphine, nephropathy, pain, podocyte, sickle cell disease