Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease

Narendranath Reddy Chintagari, Julia Nguyen, John D. Belcher, Gregory M. Vercellotti, Abdu I. Alayash

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 (50. μM heme) for 24. h. 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 (32. μM 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.

Original languageEnglish (US)
Pages (from-to)302-306
Number of pages5
JournalBlood Cells, Molecules, and Diseases
Volume54
Issue number3
DOIs
StatePublished - Mar 1 2015

Bibliographical note

Funding Information:
The authors acknowledge Dr. Dominador J. Manalo and Janvi Raichiura for help with the preliminary experiments. We acknowledge Francine Wood for providing catalase-reduced and stroma free adult human hemoglobin. We also acknowledge Bio Products Laboratory (BPL; Hertfordshire, UK) for generously providing the human haptoglobin. AIA acknowledges the support from the National Institutes of Health (NIH) under grant HL110900 and the U.S. Food and Drug Administration (MODSCI Grants). GMV and JDB were supported by a grant from NIH HL115467-01 .

Keywords

  • Haptoglobin
  • Hemeoxygenase-1
  • Kidney damage
  • Kidney proximal tubules
  • Sickle cell disease

Fingerprint Dive into the research topics of 'Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease'. Together they form a unique fingerprint.

Cite this