Research Reveals How Heme Oxygenase-1 Directs the Immune Response after Acute Kidney Injury


New research indicates that an enzyme known to be important in the body’s response to kidney injury exerts its protective effects in part by affecting the myeloid cells of the immune system. The findings, which are published in the Journal of the American Society of Nephrology, may lead to new kidney-protective treatments.

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that regulates the inflammatory response to tissue injury by converting highly reactive free heme molecules into carbon monoxide, iron, and biliverdin. People with HO-1 deficiency often experience severe hemolysis, dysregulated inflammation, kidney abnormalities, and premature death.

In an effort to uncover the effects of HO-1 after acute kidney injury (AKI), a team of researchers led by Anupam Agarwal, MD, of the University of Alabama at Birmingham, studied mice lacking expression of HO-1 systemically or in certain immune cells.

In age-matched male wild-type and HO-1–knockout mice that underwent bilateral renal ischemia for 10 minutes, ischemia-reperfusion injury resulted in significantly worse renal structure and function and increased mortality in the knockout mice. In addition, there were more macrophages and neutrophils in the knockout mice’s kidneys after ischemia-reperfusion but a significant decrease in the population of intrarenal resident dendritic cells. Immunofluorescence experiments revealed increased migration of the resident dendritic cell population from the kidneys to the peripheral lymphoid organs in knockout mice compared with wild-type mice. This effect on renal dendritic cell migration was corroborated in myeloid-specific HO-1 knockout mice subjected to bilateral ischemia. These mice also evidenced impaired kidney recovery and increased fibrosis after injury.

“We utilized HO-1 transgenic mice and cell tracking experiments to demonstrate that HO-1 expression within renal cells is important to protect in the early period after injury, while myeloid expression of HO-1 regulates how these cells traffic throughout the body after injury,” said Agarwal.

David Ferenbach, MD, PhD, who was not involved in the study and is a clinical fellow at the University of Edinburgh, noted that an accumulating field of evidence now points to the role of HO-1 as an important protector against AKI and that these latest results offer valuable new information. “Whilst not the headlined finding of the paper, important new data is shown that demonstrates that in animals with a targeted deletion of HO-1 in only myeloid cells, there is still worsened later injury and increased subsequent fibrosis compared to controls,” he said. “This validates earlier studies suggesting that despite the widespread tubular induction of HO-1 in response to drugs, the renal macrophage/dendritic cell may be the key cell population mediating the protective effects of HO-1 expression.”

Ferenbach noted that some evidence shows that aged mice have reduced levels of HO-1 in kidney cells and an increased susceptibility to renal injury. “It would be very useful to explore in human samples whether there are similar situations where HO-1 levels may fall, and whether these produce injury and scarring problems analogous to those seen in this paper,” he said.

If the study’s findings are validated in humans, HO-1 could be an important target in preventing the transition of AKI to chronic kidney disease, said Agarwal. HO-1–based treatments may also have broader clinical applications, although it is important to consider that HO-1 can have disparate functions in different cell types.

“Given the human relevance of HO-1 in AKI and the growing understanding of the myeloid cells in renal health and disease, these studies… provide the foundation for a whole new area of AKI research,” noted Gilbert Kinsey, PharmD, PhD, of the University of Virginia, in an accompanying editorial.