title: Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease.
abstract: Sickle cell disease (SCD), a hereditary hemolytic disorder is characterized by chronic hemolysis, oxidative stress, vaso-occlusion and end-organ damage. Hemolysis releases toxic cell-free hemoglobin (Hb) into circulation. Under physiologic conditions, plasma Hb binds to haptoglobin (Hp) and forms Hb-Hp dimers. The dimers bind to CD163 receptors on macrophages for further internalization and degradation. However, in SCD patients plasma Hp is depleted and free Hb is cleared primarily by proximal tubules of kidneys. Excess free Hb in plasma predisposes patients to renal damage. We hypothesized that administration of exogenous Hp reduces Hb-mediated renal damage. To test this hypothesis, human renal proximal tubular cells (HK-2) were exposed to HbA (50μM heme) for 24h. HbA increased the expression of heme oxygenase-1 (HO-1), an enzyme which degrades heme, reduces heme-mediated oxidative toxicity, and confers cytoprotection. Similarly, infusion of HbA (32μM heme/kg) induced HO-1 expression in kidneys of SCD mice. Immunohistochemistry confirmed the increased HO-1 expression in the proximal tubules of the kidney. Exogenous Hp attenuated the HbA-induced HO-1 expression in vitro and in SCD mice. Our results suggest that Hb-mediated oxidative toxicity may contribute to renal damage in SCD and that Hp treatment reduces heme/iron toxicity in the kidneys following hemolysis.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Narendranath Reddy
authors.initials: NR
authors.lastname: Chintagari
authors.affiliation: University of Minnesota, Department of Medicine, Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Minneapolis, MN 55455, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: University of Minnesota, Department of Medicine, Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Minneapolis, MN 55455, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.affiliation: University of Minnesota, Department of Medicine, Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Minneapolis, MN 55455, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: abdu.alayash@fda.hhs.gov.
authors.forename: Abdu I
authors.initials: AI
authors.lastname: Alayash
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006242:Haptoglobins / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006441:Hemoglobin A / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000166:cytology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress
chemical_list: D006242:Haptoglobins; D006441:Hemoglobin A; D051547:Heme Oxygenase-1
keywords: Haptoglobin; Hemeoxygenase-1; Kidney damage; Kidney proximal tubules; Sickle cell disease