HO-1 in sickle cell disease
Jul 19, 2006 - 3:32:37 AM
Rochester, Minnesota -- Researchers have unexpectedly shown that sickle cell-associated kidney injury may be reduced by inhibiting the enzyme activity of a protein that commonly confers protection in other diseased states. The paper by Juncos et al., "Anomalous renal effects of tin protoporphyrin in a murine model of sickle cell disease," appears in the July issue of The American Journal of Pathology.
Sickle cell disease (SCD), which affects greater than 70,000 individuals in the US, is an inherited hemoglobin disorder that causes some red blood cells to lose their smooth round shape and assume a crescent, or sickle, shape. Sickle cells can become lodged in small capillary blood vessels, with blockage of blood flow leading to pain, stroke, and damage to most organs including the lungs, spleen, kidneys and liver.
The mechanisms underlying SCD-associated kidney disease include various forms of secondary stress, such as changes in internal kidney blood flow, induction of oxidative injury, and influx of inflammatory cells. Researchers have thought that cells combat such stress through expression of heme oxygenase-1 (HO-1), a protective enzyme that is upregulated in SCD kidneys in humans and in mouse models. New research, however, suggests that in SCD HO-1 may not be as protective as previously thought.
In an attempt to understand the specific role of HO-1 in kidney injury, Juncos et al. examined SCD mice in the presence or absence of tin protoporphyrin (SnPP), a widely accepted inhibitor of the enzyme activity of HO. Short-term SnPP treatment successfully blocked HO activity in both normal and SCD mice, reduced kidney blood flow in normal and SCD mice, but did not affect the filtration capacity of the kidney in either group. However, when chronically administered, SnPP caused inflammation and fibrosis (scarring) in normal mice but not in SCD mice; in normal mice, SnPP induced genes related to fibrosis and inflammation, whereas in SCD mice, these genes were downregulated.
The scientists next examined the effect of SnPP on kidney injury induced by temporarily interrupting kidney blood flow (ischemia); the kidney in SCD mice is hypersensitive to such ischemia. Surprisingly, when mice were treated with SnPP, SCD kidneys were protected from ischemia-induced cell death and blood vessel blockage whereas normal kidneys exhibited cell death and injury. Thus, in contrast with its effects observed in normal mice, SnPP protected SCD kidneys from injury.
In other diseases, induction of HO-1 is protective by generating products such as carbon monoxide and bile pigments, both of which can reduce tissue injury; however, in larger amounts, these products may be toxic. It is possible that the degree of induction of HO-1 in SCD may generate toxic rather than protective amounts of these products. Additionally, along with its intended effect of inhibiting HO activity, SnPP may induce HO-1 protein, and this latter effect may underlie the observed cytoprotection. Finally, besides inhibiting HO activity, SnPP may concomitantly interrupt other pathways, independent of the HO system, that contribute to kidney injury in SCD.
In the process of analyzing the biologic significance of HO-1 in SCD, Juncos et al. uncovered an experimental strategy that reduced kidney injury in a mouse model of SCD. Further work will likely delineate the basis for the protective effects of SnPP in SCD, specifically, the dependency on inhibition of HO activity, increase in HO-1 protein, or some other as-yet-undefined mechanism.
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