The roles of heme oxygenase-1 in renal disease

Abstract

Heme oxygenase (HO), a heat shock protein containing hemoglobin, is an important enzyme in heme catabolism. It is involved in cell homeostasis and has anti-inflammatory, antioxidant, anti-apoptosis, immunomodulation, and other functions. It is expressed at a modest level in most normal tissues. When the body suffers from ischemia hypoxia, injury, toxins, and other nociceptive stimuli, the expression increases, which can transform the oxidative microenvironment into an antioxidant environment to promote tissue recovery from damage. In recent years, research has continued to verify its value in a variety of human bodily systems. It is also regarded as a key target for the treatment of numerous disorders. With the advancement of studies, its significance in renal disease has gained increasing attention. It is thought to have a significant protective function in preventing acute kidney injury and delaying the progression of chronic renal diseases. Its protective mechanisms include anti-inflammatory, antioxidant, cell cycle regulation, apoptosis inhibition, hemodynamic regulation, and other aspects, which have been demonstrated in diverse animal models. Furthermore, as a protective factor, its potential therapeutic efficacy in renal disease has recently become a hot area of research. Although a large number of preclinical trials have confirmed its therapeutic potential in reducing kidney injury, due to the problems and side effects of HO-1 induction therapy, its efficacy and safety in clinical application need to be further explored. In this review, we summarize the current state of research on the mechanism, location, and treatment of HO and its relationship with various renal diseases.

Keywords: heme oxygenase; mechanism; renal disease; therapeutic; value.

Figure 1

Describes how oxidative stress injury induced HO-1 expression and its function mechanism. Stimulation such as ischemia, anoxic, and injury leads to the generation of ROS, further activates PKC and MAPK protein kinases, dissociates Nrf2 from keap-1, and binds the activated Nrf2 to ARE protein, thus inducing the increase of HO-1 expression. HO-1 promotes the body to recover from injury through various mechanisms such as anti-inflammation, antioxidative stress, cell cycle regulation, anti-apoptosis, etc. (This article introduces its role and mechanism in detail). Secondly, its heme-decomposing products CO, Fe²⁺, and biliverdin also play a role in cell protection by regulating antioxidants, inhibiting iron accumulation in cells, and regulating the secretion of inflammatory mediators. PKC, protein kinase C; MAPK, mitogen- activated protein kinase; AP-1, activator protein 1; Nrf2, NF -E2-related factor 2; ARE, antioxidant response element; Keap-1, Kelch-like ECH- -associated protein-1; NF -kB, nuclear factor-k-gene binding; CDK, Cyclin dependent kinase; ROS, reactive oxygen species; NOS, nitric oxide synthase; COX-2, cyclooxygenase-2.

Figure 2

The expression and function of HO-1 is different in different parts of the kidney. The renal tubular epithelial cells have the strongest ability to express HO-1. When injury occurs, ROS in cells increases, and heme binds to the TLR4 receptor on tubule epithelium to promote HO-1 expression. HO-1 upregulates CDK inhibitor P21, reduces tubular cell apoptosis, and inhibits proximal tubular autophagy. In addition, injury can also induce HO-1 expression in podocytes, mesangial cells, and endothelial cells in an Nrf2-dependent manner, regulate complement activation and thrombomodulin, mediate inflammation and thrombosis, and protect cells. ROS, reactive oxygen species; TLR4, Toll-like receptor 4; CDK, Cyclin dependent kinase; NOS, nitric oxide synthase.