The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury

Abstract

Heme oxygenases (HOs) catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, the latter of which is subsequently converted to bilirubin by biliverdin reductase. Recent attention has focused on the biological effects of product(s) of this enzymatic reaction, which have important antioxidant, anti-inflammatory, and cytoprotective functions. Two major isoforms of the HO enzyme have been described: an inducible isoform, HO-1, and a constitutively expressed isoform, HO-2. A third isoform, HO-3, closely related to HO-2, has also been described. Several stimuli implicated in the pathogenesis of renal injury, such as heme, nitric oxide, growth factors, angiotensin II, cytokines, and nephrotoxins, induce HO-1. Induction of HO-1 occurs as an adaptive and beneficial response to these stimuli, as demonstrated by studies in renal and non-renal disease states. This review will focus on the molecular regulation of the HO-1 gene in renal injury and will highlight the interspecies differences, predominantly between the rodent and human HO-1 genes.

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

“…HO-1 expression is inducible, while HO-2 expression is constitutive [162]. The expression of each gene differs by cell type, tissue distribution and regulation [163].…”

“…The regulation of HO-1 expression in mammalian cells is very complex. HO-1 is induced by many factors, such as hypoxia, hydrogen peroxide, heavy metals, heme and depletion of cellular glutathione [162,164]. The regulation of HO-1 expression by these factors is not only cell type-dependent but also species-dependent [162,164].…”

“…HO-1 is induced by many factors, such as hypoxia, hydrogen peroxide, heavy metals, heme and depletion of cellular glutathione [162,164]. The regulation of HO-1 expression by these factors is not only cell type-dependent but also species-dependent [162,164]. For example, hypoxia induces HO-1 expression in rodent, bovine and monkey cells, but represses HO-1 expression in several human cell lines, including lung cancer A549 cells, umbilical vein endothelial cells and glioblastoma cells [72,[165][166][167][168][169][170].…”

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

“…Although the precise mechanisms by which HO-1 exerts its cytoprotective effects are not known, there is mounting evidence that carbon monoxide plays a key role in this process. For thorough reviews of the recent literature see [17,18].Another characteristic of oxidative stress is the formation of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). HNE has been shown to increase HO-1 in the cell [19,20], but the mechanism(s) has not been clearly defined.…”

“…Although the precise mechanisms by which HO-1 exerts its cytoprotective effects are not known, there is mounting evidence that carbon monoxide plays a key role in this process. For thorough reviews of the recent literature see [17,18].…”