GATA2 promotes oxidative stress to aggravate renal ischemia-reperfusion injury by up-regulating Redd1

Acute kidney injury (AKI) is a common clinical emergency, during which kidney cells are damaged by various causes, and it is a complex pathophysiological process (Sun et al., 2019). Despite the multifarious causes, it is generally believed that renal ischemia-reperfusion injury (RIRI) is the most essential pathogenesis of AKI (Zhao et al., 2018). Kidney is a highly perfused organ, for this reason, kidney is easily damaged by ischemia and reperfusion (Liu and Yang, 2019). RIRI refers to a pathological phenomenon that blood perfusion of kidney tissue is interrupted or sharply reduced, causing ischemic injury; moreover, after the blood flow is restored, the kidney function and tissue damage are further aggravated (Liu et al., 2019, Isenberg and Roberts, 2019). RIRI will cause the destruction of renal microstructure and even the damage of kidney function (Lambert and Schlaich, 2017). However, the complicated pathogenesis of RIRI confers difficulty to treatments, and current medical strategies are deficient in diagnosis of RIRI. Ascribed to the above reasons, it is necessary to understand more molecular mechanisms by RIRI.

At present, a large number of studies have shown that RIRI is closely related to the production of oxygen free radicals, intracellular calcium overload, inflammatory response, and cell apoptosis (Aboutaleb et al., 2019, Erpicum et al., 2018, He et al., 2018). Among them, oxidative stress (OS) plays a crucial role in the occurrence and development of RIRI (Wang et al., 2020). Some studies have demonstrated that IR induced severe OS to destroy cellular homeostasis, and further damage organs through the production of oxygen free radicals, such as reactive oxygen species (ROS) (Diao et al., 2019). ROS are highly active signaling molecules that maintain the redox homeostasis of mammalian cells (Zhang et al., 2021). Under normal physiological conditions, cells produce little amount of ROS (Francis and Baynosa, 2017). However, the disorder of redox homeostasis under pathological conditions causes the excessive production of ROS, which ultimately leads to OS and oxidative damage of cell components (Yin et al., 2017). Maria V et al. clarified that elevated level of renal ROS can lead to lipid oxidation, therefore leading to cell damage and abnormal renal functions (Irazabal and Torres, 2020). It is worth noting that ROS plays a vital role in tissue damage and cell apoptosis during RIRI (Qu and Zhang, 2020). A large number of experimental studies have shown that after kidney tissues undergo ischemia/reperfusion, a large amount of ROS will be produced, causing the OS response of the kidney, which is one of the important mechanisms leading to RIRI (Zhao et al., 2020, Zhang et al., 2020, Lorenzen et al., 2013).

Protein Regulated In Development And DNA Damage Response 1 (Redd1) is a common stress response element and is involved in the occurrence and development of diverse diseases, including oxygen-glucose deprivation and hypoxia (Britto et al., 2020). Recently, the functions of Redd1 have attracted increasing attention during the injury process (Li et al., 2019a). Previous studies have shown that Redd1 may regulate IR-induced neuronal OS damage by mediating mTOR signaling in cerebral ischemic diseases (Seong et al., 2019). In addition, some studies have found that Redd1 is also related to the production of ROS. Gao et al. found that Redd1 knockdown significantly reduced ROS production and reduced myocardial IR injury in mice (Gao et al., 2020). Cho et, al. showed that Redd1 plays an important role in oxidative stress-mediated liver cell damage (Cho et al., 2018). However, the function of Redd1 in RIRI has not been reported.

GATA binding protein 2 (GATA2) is a zinc finger-containing transcription factor and is considered to be a key regulator of hematopoietic development and maintenance of hematopoietic stem cells (Moriguchi, 2021). It’s reported that GATA2 is highly expressed in urogenital primordial tissue in early embryogenesis and plays an important role in renal development (Estrela et al., 2021). Yu L et al. showed that the transcription factor GATA2 is specifically expressed in collecting duct cells and promoted the progression of RIRI through upregulating inflammatory cytokine gene expression (Yu et al., 2017). However, the potential possibility of interaction between GATA2 and Redd1 remains unknown.

Therefore, this experiment used hypoxia/reoxygenation (HR) cell model and RIRI mice model to detect the expression level and molecular mechanism of Redd1 involved in RIRI. We demonstrate a novel mechanism underlying of RIRI that GATA2 increased Redd1 in oxidative stress by promoting the transcription of Redd1, thereby aggravating RIRI.

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