Heme protein-induced chronic renal inflammation: Suppressive effect of induced heme oxygenase-1

Karl A. Nath, Gregory M. Vercellotti, Joseph P. Grande, Hiroko Miyoshi, Carlos V. Paya, J. Carlos Manivel, Jill J. Haggard, Anthony J. Croatt, William D. Payne, Jawed Alam

Research output: Contribution to journalArticlepeer-review

198 Scopus citations


Background: Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme; its inducible isozyme, HO-1, protects against acute heme protein-induced nephrotoxicity and other forms of acute tissue injury. This study examines the induction of HO-1 in the kidney chronically inflamed by heme proteins and the functional significance of such an induction of HO-1. Methods: Studies were undertaken in a patient with chronic tubulointerstitial disease in the setting of paroxysmal nocturnal hemoglobinuria (PNH), in a rat model of chronic tubulointerstitial nephropathy caused by repetitive exposure to heme proteins, and in genetically engineered mice deficient in HO-1 (HO-1 -/-) in which hemoglobin was repetitively administered. Results: The kidney in PNH evinces robust induction of HO-1 in renal tubules in the setting of chronic inflammation. The heme protein-enriched urine from this patient, but not urine from a healthy control subject, induced expression of HO-1 in renal tubular epithelial cells (LLC-PK1 cells). A similar induction of HO-1 and related findings are recapitulated in a rat model of chronic inflammation induced by repetitive exposure to heme proteins. Additionally, in the rat, the administration of heme proteins induces monocyte chemoattractant protein (MCP-1). The functional significance of HO-1 so induced was uncovered in the HO-1 knockout mouse: Repeated administration of hemoglobin to HO-1 +/+ and HO-1 -/- mice led to intense interstitial cellular inflammation in HO-1 -/- mice accompanied by striking up-regulation of MCP-1 and activation of one of its stimulators, nuclear factor-κB (NF-κB). These findings were not observed in similarly treated HO-1 +/+ mice or in vehicle-treated HO-1 -/- and HO-1 +/+ mice. Conclusion: We conclude that up-regulation of HO-1 occurs in the kidney in humans and rats repetitively exposed to heme proteins. Such up-regulation represents an anti-inflammatory response since the genetic deficiency of HO-1 markedly increases activation of NF-κB, MCP-1 expression, and tubulointerstitial cellular inflammation.

Original languageEnglish (US)
Pages (from-to)106-117
Number of pages12
JournalKidney international
Issue number1
StatePublished - Jan 2001


  • Monocyte chemoattractant protein-1
  • Nuclear factor-κB
  • Paroxysmal nocturnal hemoglobinuria
  • Tubulointerstitial inflammation


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