Advances in oxidative stress and NOD-like/toll-like receptors in acute renal injury

Tian-Yu Xia, Xiao-Lin Zhang, Di Li, Wen-Li Liu, Zhi-Cheng Tan

1. The second hospital of shanxi medical university, Taiyuan 030001, China

2. Department of Nephrology, Wujiaqui People's Hospital, Urumqi 831100, China 3. Department of Nephrology, Shanxi Provincial People's Hospita

Keywords:Oxidative stress Innate immune receptors Acute renal injury

ABSTRACT Acute Kidney Injury (AKI) is a clinical syndrome characterized by rapid renal deterioration with high morbidity and mortality. Renal reperfusion (IRI), renal toxicity and sepsis are the main causes of AKI. IRI is one of the main causes of acute kidney injury in clinic, accounting for 75% of all the causes of AKI [1]. The fatality rate of AKI caused by IRI is high, and the surviving patients may leave chronic renal impairment with different degrees [2]. A number of studies have shown that ischemia-reperfusion injury leading to renal dysfunction is directly related to oxidative stress, and the inhibition of oxidative stress through nod-like/toll-like signaling pathway can reduce acute renal injury. This review summarizes the research progress in regulating oxidative stress and the relationship between innate immune receptors and acute renal injury.

The kidney is a highly sensitive organ and ischemia can cause ischemic kidney injury. After early kidney ischemia, the body will repair the damage by itself after reperfusion [1]. With prolonged ischemic time, renal tubular epithelial cells will undergo irreversible damage, eventually necrosis and shedding of the renal tubules [2]. Reperfusion is a necessary condition for the recovery of renal function, but the sudden restoration of blood supply will also cause long-term damage to the kidney. Acute kidney injury (AKI) is a clinical syndrome that occurs due to a rapid decline in renal function caused by various causes. In China and even the world, AKI is a critical illness with poor clinical prognosis and lack of effective treatment [3,4]. Ischemia-reperfusion injury (IRI) refers to the process of temporary loss of blood flow and tissue perfusion followed by a return to its original state. Transient IRI is less likely to cause permanent damage, but the sensitivity will be different for different target cells and tissues, and the kidney is sensitive to ischemia and ischemia-reperfusion [5]. So far, the molecular mechanism of AKI is not clear, but there is increasing evidence that IRI is one of the most researched diseases directly related to oxidative stress.

1. Oxidative stress

Reactive oxygen species (ROS) are chemical groups that have a strong ability to compete for the electrons of surrounding chemical groups. As a substance necessary for maintaining life, ROS can participate in a variety of normal physiological reactions such as aerobic metabolism and inflammatory response. Oxidative stress refers to a stress state in which excessive ROS generation, weakened antioxidant capacity, and imbalance of the body's own oxidation / reduction dynamic balance cause oxidative damage to a variety of biological macromolecules, which seriously affects normal life activities [6]. Excessive ROS triggers lipid peroxidation, endothelial cell and cellular DNA damage, and inactivation of antioxidant enzymes, which further aggravate kidney damage.

Elevated levels of oxidative stress in ischemia-reperfusion injury are related to the activation of NADPH oxidase. NADPH oxidase (Nox) is the main enzyme body that generates ROS during ischemiareperfusion injury. [7] Nox4 is expressed at high levels in the kidney, Nox1, Nox2 and other Nox subunits are meaningfully expressed in the kidney, and they are the source of renal ROS production [8]. ROS produced by NADPH oxidase is involved in mediating many signaling pathways in cells, and plays an important role in regulating the signaling of cell growth, division, proliferation, differentiation, apoptosis and immune defense. In the state of ischemia-reperfusion, the kidney can activate NOX2 and NOX4, and induce a large amount of ROS. ROS not only directly affects the kidney, induces apoptosis of tubules and mesangial cells, but also activates the PCK and MAPK pathways, thereby activating NF-κB, and mediates multiple inflammatory cytokines such as IL-1 and TNF -α, causes pathological changes and apoptosis in the kidney, and aggravates kidney damage [9].

Hydrogen sulfide (H2S) has the effects of relaxing vascular smooth muscle, resisting ischemia and hypoxia, and neuroprotection. It also plays a role in regulating many physiological processes such as cell proliferation, necrosis, oxidative stress, inflammation, and metabolism. Participated in the occurrence and development of cardiovascular, respiratory, neurological, endocrine and other systemic diseases. Although the mechanism of action of H2S is unclear, its clinical value has been recognized. There are generally two forms of H2S in the body, 1/3 is gas H2S, and 2/3 is NaHS. The two form a dynamic balance in the body. NaHS dissociates into sodium ions (Na +) and sulfhydryl ion (HS-) in the body. HS- combines with H + in the body to form H2S.

Pharmacological experiments show that exogenous H2S is involved in kidney self-repair and significantly improves the ultrastructure of mouse kidney tissue. Analysis of H2S may exert protective effects on the kidney in the following ways [10]: ① H2S can [7] inhibit the activation of NOX2 and NOX4 in kidney IRI, reduce the production of ROS, and enhance the kidney's anti-oxidation and anti-apoptosis capabilities, thereby It can reduce kidney damage caused by oxidative stress and has protective effect on renal IRI. ② Reduce renal IRI by enhancing autophagy. Animal experiments have shown that treating mice with exogenous H2S can significantly improve renal structural lesions and renal function, increase the antioxidant capacity of the kidney tissue and scavenge free radicals, and increase renal autophagy.

2. Innate immune system-mediated inflammation

The innate immune system exists in almost all organs and triggers immune inflammatory responses through pattern recognition receptors (PRRs), which play an important role in tissue damage. Toll-like receptors (TLRs) and NOD-like receptors (NLRs) on the membrane surface are pattern recognition receptors (PRRs) that act as signal molecules in the body. There are more than 20 Toll-like receptors (membrane-bound) and NOD-like receptors (cytoplasm) in humans working together to produce the correct immune response. NLRs are an important member of intracellular pattern recognition receptors. The NLRP3 inflammatory bodies can activate caspase-1, and through ASC and caspase-1, trigger the secretion of proinflammatory cytokines such as IL-1 and IL-18. Involved in the body's immune response against pathogens, overexpression of IL-18 increases neutrophil infiltration and aggravates renal damage [11].

Toll-like receptors (TLR) are considered to be the first line of defense against invading microorganisms, and their expression can be rapidly regulated by pathogens, a variety of cytokines, and environmental stressors [12-14]. The TLR family signaling mechanism mainly depends on the adaptor molecules and kinases in the cytoplasmic region. According to the different linker proteins, they can be divided into MYD88 and non-MYD88-dependent pathways, both of which can induce NF-κB signaling pathway activity, further induce the expression of related genes such as IL-1β, and then increase renal damage [15,16]. Therefore, the TLR family plays an important role in the induction of the NF-κB signaling pathway, and at the same time can regulate the expression of multiple genes involved in the immune response [17,18].

NOD-like receptors are involved in the physiological processes of many diseases, such as diabetes, acute kidney injury, chronic obstructive kidney disease, gout, inflammatory kidney disease, allergies, viral infections, and tumors. NOD1 and NOD2 receptors are the earliest intracellular PRRs found in the NLRs family and play important roles in inflammatory response and immune regulation. Their structures are basically the same. By binding to related signaling proteins, they activate signal pathways such as MAPK, JNK, and NF-κB, and promote the secretion of cytokines such as TNF-α, IL-6, and IL-8, thereby participating in the immune response.

TLRs signaling pathways mediate various kidney diseases such as nephritis, acute kidney injury, and renal transplant rejection. TLR2 and TLR4 on renal tubular epithelial cell membranes recognize damage-related molecular patterns such as HSPgp96, activate NFκB, induce the expression of MCP-1, IL-6, and IL-1β, and attract macrophages and neutrophils into the kidney. After ischemiareperfusion, dendritic cells accumulate in the kidney, mature dendritic cells secrete a variety of cytokines such as INF-γ, IL-6, and IL-12, and promote the activation and migration of macrophages and neutrophils Initiating adaptive immunity [19]. In addition, TLR4 can also regulate the activation of immune cells such as NK cells and γ T cells, and enhance the expression of adhesion molecules CD62E and CD54 [20].

3. Oxidative stress and NOD / Toll-like receptor signaling pathway

Oxidative stress plays an important role in the occurrence and development of IRI, and its induced ROS is an important factor in promoting renal tubular injury. The study found that the expression of NOD1 and NOD2 increased significantly after the occurrence of IRI. However, pretreatment with exogenous H2S before ischemia can effectively inhibit the expression of the above-mentioned inflammatory factors and reduce the damage to the kidney and renal function. When the production of ROS is suppressed or eliminated, the oxidative stress of renal tubular epithelial cells is also suppressed, thereby inhibiting the apoptosis of epithelial cells.

Activation of NLRP3 inflammatory bodies includes initiation and activation. Initiation is dependent on NF-κB NLRP3 transcription. The NLRP3 transcription step requires ROS-sensitive proinflammatory signals, and the transcription step can be blocked by ROS scavengers. Renal ischemia-reperfusion injury will act as a stimulus to activate more ROS production, which will trigger the initiation and activation of NLRP3. The NLRP3 inflammatory bodies can further activate caspase-1, leading to apoptosis. Pharmacological experiments have found that in kidney tissue of IRE rats, inhibiting the expression of NLRP3 inflammasome can effectively reduce kidney damage [21].

Membrane surface Toll-like receptors are distributed on renal tubular epithelial cell membranes. Studies have shown that [22], renal IRI is related to TLR2 and TLR4. Renal IRI is activated in renal epithelial cells. The specific manifestation is that after ischemia-reperfusion, TLR2 and TLR4 on renal tubular epithelial cell membranes will recognize molecular patterns related to injury, thereby activating NFκB and inducing IL-1β , IL-6, MCP-1, TNF-a expression, which induces neutrophils and macrophages into the kidney after ischemia, promotes inflammatory response and apoptosis, causing acute tubular interstitial damage [23] .

4. Outlook

In summary, we found that the activation of renal TLR2 / TLR4, NOD1 / NOD2 receptors can trigger many intracellular pathways, such as NF-?B, mitogen-activated protein kinase, c-Jun N-terminal kinase, etc., and promote chemokines And the release of proinflammatory cytokines, these signaling pathways function in both local and distal organs, establishing a systemic inflammatory state and greatly exacerbating the clinical situation. Therefore, blocking or inactivation of the innate immune receptor pathway can prevent or alleviate AKI [24]. Current studies have shown that the activation of TLR2 / TLR4, NOD1 / NOD2 receptors in renal ischemiareperfusion injury can be inhibited by regulating the oxidative stress pathway, thereby reducing the inflammatory response and apoptosis in renal ischemia-reperfusion [25] . H2S can inhibit the activation of NOX2 and NOX4 in kidney IRI and reduce the production of ROS. At the same time, because the antioxidant function of H2S involves glutathione, the potential mechanism of transsulfur signal and sulfur-containing molecules including cysteine molecules may help elucidate the antioxidant function. The current conclusion is obtained from animal experiments, so in order to further understand the pathophysiological pathway of ischemia-reperfusion acute kidney injury and to determine the possible therapeutic use of H2Smediated antioxidant function, more thorough experimental and clinical research is necessary.