Immunomodulatory Effects of Heme Oxygenase-1 in Kidney Disease

Abstract

Kidney disease is a general term for heterogeneous damage that affects the function and the structure of the kidneys. The rising incidence of kidney diseases represents a considerable burden on the healthcare system, so the development of new drugs and the identification of novel therapeutic targets are urgently needed. The pathophysiology of kidney diseases is complex and involves multiple processes, including inflammation, autophagy, cell-cycle progression, and oxidative stress. Heme oxygenase-1 (HO-1), an enzyme involved in the process of heme degradation, has attracted widespread attention in recent years due to its cytoprotective properties. As an enzyme with known anti-oxidative functions, HO-1 plays an indispensable role in the regulation of oxidative stress and is involved in the pathogenesis of several kidney diseases. Moreover, current studies have revealed that HO-1 can affect cell proliferation, cell maturation, and other metabolic processes, thereby altering the function of immune cells. Many strategies, such as the administration of HO-1-overexpressing macrophages, use of phytochemicals, and carbon monoxide-based therapies, have been developed to target HO-1 in a variety of nephropathological animal models, indicating that HO-1 is a promising protein for the treatment of kidney diseases. Here, we briefly review the effects of HO-1 induction on specific immune cell populations with the aim of exploring the potential therapeutic roles of HO-1 and designing HO-1-based therapeutic strategies for the treatment of kidney diseases.

Different Acute Kidney Injury Patterns after Renal Ischemia Reperfusion Injury and Extracorporeal Membrane Oxygenation in Mice

“…HO-1 can be expressed in renal tubular epithelial cells and leukocytes in response to oxidative stress [ 17 ] and hemolysis [ 18 , 19 ]. Macrophages are the pre-dominantly HO-1 expressing cells [ 19 ].…”

“…HO-1 can be expressed in renal tubular epithelial cells and leukocytes in response to oxidative stress [ 17 ] and hemolysis [ 18 , 19 ]. Macrophages are the pre-dominantly HO-1 expressing cells [ 19 ]. HO-1 expression in the kidney was determined by immunofluorescence after moderate and severe renal IRI and different time-points after ECMO.…”

“…In contrast to the HO-1 expression in renal tubular cells following ECMO, HO-1 was expressed on cells located in the tubulo-interstitial space after renal IRI. Previous studies have shown that HO-1 is expressed on a different myeloid cells including neutrophils, dendritic cells, and macrophages after renal IRI [ 19 ]. Moreover, HO-1 expressing myeloid cells promoted resolution of inflammation and recovery in ischemic AKI [ 17 ].…”

The Role of Heme Oxygenase-1 as an Immunomodulator in Kidney Disease

“…Free heme influences innate immune responses through the activation of Toll-like receptor 4 and ROS-dependent pathways, which in turn, through complex signaling pathways, promote the expression of proinflammatory cytokines. In addition, heme degradation byproducts (CO, biliverdin, bilirubin) and HO-1 constitute key molecules that upregulate the secretion of anti-inflammatory cytokines, such as IL-10 [ 13 ] ( Figure 2 ). On the other hand, many pro-inflammatory enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), are in fact hemoproteins whose functions may be impaired due to insufficient free heme once that heme has been catalyzed by HO-1 [ 14 ].…”

“…Μonocytes from patients with SLE—independently of disease activity—displayed significantly reduced HO-1 levels compared to those of healthy controls, suggesting that this low HO-1 expression and action could contribute to altered monocyte function in SLE and lupus nephritis. [ 13 ]. Kishimoto et al have also demonstrated that glomerular M2-like macrophages from LN patients exhibit lower levels of HO-1 expression.…”