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

Background. Heme oxygenase (HP) is the rate-limiting enzyme in the degradat ion of heme; its inducible isozyme, HO-1, protects against acute heme prote in-induced nephrotoxicity and other forms of acute tissue injury. This stud y 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 tubulointerstiti al 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 tubule s in the setting of chronic inflammation. The heme protein-enriched urine f rom this patient, but not urine from a healthy control subject, induced exp ression of HO-1 in renal tubular epithelial cells (LLC-PK1 cells). A simila r induction of HO-1 and related findings are recapitulated in a rat model o f chronic inflammation induced by repetitive exposure to heme proteins. Add itionally, in the rat, the administration of heme proteins induces monocyte chemoattractant protein (MCP-1). The functional significance of HO-1 so in duced was uncovered in the HO-1 knockout mouse: Repeated administration of hemoglobin to HO-1 +/+ and HO-1 -/- mice led to intense interstitial cellul ar inflammation in HO-1 -/- mice accompanied by striking up-regulation of M CP-1 and activation of one of its stimulators, nuclear factor-KB (NF-KB). T hese findings were not observed in similarly treated HO-1 +/+ mice or in ve hicle-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 r epresents an anti-inflammatory response since the genetic deficiency of HO- 1 markedly increases activation of NF-kappaB, MCP-1 expression, and tubuloi nterstitial cellular inflammation.