title: HO-1 expression control in the rat glomerulus.
abstract: The differential localization of HO-1 in renal cells under conditions of injury, and the demonstration that exaggerated HO-1 expression can have detrimental rather than beneficial effects, raises the question of whether HO-1 expression in these cells is subject to control. The present study identifies a unique HO-1 expression pattern in the renal glomerulus indicative of presence of HO-1 expression control following prolonged HO-1 induction. HO-1 and HO-2 expression in response to the natural HO substrate/inducer Fe(++) protoporphyrin (PP) IX (hemin) was assessed in normal rat glomeruli. Following 18 h incubations with hemin (0-200 μM), HO-1 expression increased in a concentration-dependent manner and via a hemopexin (HPX) independent mechanism with no effect on HO-2. In incubations with higher hemin concentrations (400 μM), likely to be encountered in hemolytic disorders, HO-1 expression, decreased. This was preceded by a prolonged and sustained increase in HO-1 protein and was independent of the Fe(++) moiety as incubations with Cobalt protoporphyrin (CoPP) resulted in an identical expression pattern. The decrease of HO-1 protein could not be accounted for by proteasomal degradation since it was not reversed in co-incubations with hemin and the proteasome inhibitor, MG132, at concentrations sufficient to increase HO-1 glomerular content when used alone. Moreover, in the presence of MG132, a decrease of HO-1 expression also occurred at 100 and 200 μM hemin. The effect of MG132 was mimicked by two additional mechanistically different approaches which also raised HO-1 content: a) co-incubations of hemin with ZnPP which increased HO-1 protein when used alone, and b) glomerular HO-1 over expression achieved by SB transposon mediated transgenesis. In contrast, the decrease in HO-1 levels observed at high hemin concentrations was reversed in co-incubations with hemin and SnPP, which reduced HO-1 content when used alone. Expression of NF-E2 related factor 2 (Nrf2) protein, which mediates HO-1 induction in response to hemin, had a similar expression pattern with that of HO-1 protein indicating involvement of Nrf2 in the response of HO-1 to hemin. The above observations indicate presence of a HO-1 expression control mechanism in the glomerulus that may serve to protect it against potentially detrimental effects of exaggerated HO-1 expression.
authors.affiliation: 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University of Athens School of Medicine, GP Livanos and M. Simou Laboratories, Athens, Greece. Electronic address: mdetsika@med.uoa.gr.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Detsika
authors.affiliation: Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, New Brunswick, NJ, United States.
authors.forename: Pu
authors.initials: P
authors.lastname: Duann
authors.affiliation: 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University of Athens School of Medicine, GP Livanos and M. Simou Laboratories, Athens, Greece; Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, New Brunswick, NJ, United States.
authors.forename: Elias A
authors.initials: EA
authors.lastname: Lianos
mesh_terms: D000818:Animals; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006427:Hemin / Q000008:administration & dosage; D007678:Kidney Glomerulus / Q000201:enzymology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006427:Hemin; D051547:Heme Oxygenase-1
keywords: Expression; Glomerulus; Heme oxygenase (HO)-1; Metalloporphyrins