Heme protein-induced chronic renal inflammation: suppressive effect of induced heme oxygenase-1.
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-kappaB (NF-kappaB). These findings were not observed in similarly treated HO-1 +/+ mice or in vehicle-treated HO-1 -/- and HO-1 +/+ mice.


CONCLUSIONS
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-kappaB, MCP-1 expression, and tubulointerstitial cellular inflammation.
Nath
K A
KA
Nephrology Research Unit, Departments of Pathology and Immunology, Mayo Clinic/Foundation, Rochester, MN 55905, USA.
Vercellotti
G M
GM
Grande
J P
JP
Miyoshi
H
H
Paya
C V
CV
Manivel
J C
JC
Haggard
J J
JJ
Croatt
A J
AJ
Payne
W D
WD
Alam
J
J
D000328:Adult; D000818:Animals; D002908:Chronic Disease; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D006418:Heme / Q000494:pharmacology / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D006457:Hemoglobinuria, Paroxysmal / Q000201:enzymology; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009393:Nephritis / Q000209:etiology*; D051381:Rats; D015854:Up-Regulation
D008565:Membrane Proteins; D006418:Heme; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse