Heme oxygenase is induced in nephrotoxic nephritis and hemin, a stimulator of heme oxygenase synthesis, ameliorates disease.
Heme oxygenase (HO) catalyses degradation of heme to biliverdin, iron and carbon monoxide (CO). Two isoforms exist, a constitutive form and an inducible form (HO-1). Induction of HO-1 may have protective effects in inflammation. We studied heterologous (HNTN) and accelerated (ANTN) nephrotoxic nephritis in Lewis rats. Hemin, an inducer of HO-1, (30 mumol/kg) was administered 18 hours before induction of nephritis and 72 hours later in ANTN. HO-1 was not detected immunohistochemically in normal glomeruli but was present in HNTN and ANTN in cells with the morphology of macrophages. HO-1 induction was confirmed by RT-PCR. In normal rats hemin induced glomerular HO-1 mRNA at 18 hours. In HNTN hemin markedly reduced proteinuria at 24 hours (10 +/- 4 mg/24 hr; control 54 +/- 16; P < 0.05), neutrophil infiltration at two hours (29.8 +/- 1.8 vs. 22.3 +/- 1.5 neutrophils/glomerulus, P < 0.05), and glomerular macrophage number at two hours (2.1 +/- 0.1 vs. 3.1 +/- 0.4 cells/glomerulus, P < 0.05). In ANTN proteinuria was reduced at day 1 and day 4 (36 +/- 11 vs. 60 +/- 15 and 36 +/- 7 vs. 86 +/- 9 mg protein/24 hr, respectively, P < 0.001), glomerular thrombi were reduced by hemin at day 1 and 4 (1.5 +/- 2.7 vs. 2.7 +/- 0.2 and 1.3 +/- 0.01 vs. 2.9 +/- 0.02, respectively, P < 0.001) and glomerular macrophage infiltration was reduced on day 4 (11.2 +/- 0.8 cells/glom; control 15.9 +/- 0.8, P < 0.01). Possible mechanisms by which HO-1 ameliorates disease include anti-complement or anti-oxidant effects of bilirubin and vasodilator and anti-platelet effects of carbon monoxide.
Mosley
K
K
Department of Histopathology and Experimental Pathology, Imperial College School of Medicine at St Mary's, London, England, United Kingdom.
Wembridge
D E
DE
Cattell
V
V
Cook
H T
HT
D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005921:Glomerulonephritis / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology*; D007150:Immunohistochemistry; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D012333:RNA, Messenger; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1