Corrigendum: Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury

Qiao Tang¹Jiatao Xie²Yifei Wang¹Chong Dong^3,4*Qian Sun^1*

• ¹Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
• ²The First Clinical College of Wuhan University, wuhan, China
• ³Organ Transplantation Center, Tianjin First Central Hospital, TianJin, China
• ⁴Tianjin Key Laboratory for Organ Transplantation, TianJin, China

1Introduction Severe renal ischemia and reperfusion injury (IRI) is a risk factor for the development and progression of chronic kidney disease (CKD) and end-stage renal disease, which will further increase the global morbidity and mortality(1). Long-term IRI causes persistent non-specific inflammation, drives immune cell infiltration and cytokine release, and causes excessive accumulation of extracellular matrix, which leads to irreversible renal interstitial fibrosis (RIF) and decreases the long-term survival rate of transplanted kidney(2,3). Persistent inflammation and RIF are two pathophysiological processes involved in the maladaptive repair process of IRI to CKD transformation(4,5). During IRI-related RIF, severe and persistent inflammatory injury leads to excessive repair of M2 macrophages, which not only releases more pro-fibrotic factors to further activate myofibroblasts, but also encourages macrophages to directly transform into myofibroblasts(6). Therefore, macrophage polarization and its functional diversity are important factors of IRI-related RIF in transplanted kidney. Activation transcription factor 3 (ATF3) is a basic leucine zipper (bZIP) DNA binding protein induced by oxidative stress and a member of the transcription factor family of ATF/cAMP responsive element binding proteins. In recent years, studies on fibrosis of heart, liver, lung and other organs have shown that ATF3 could accelerate extracellular matrix accumulation and down-regulation of ATF3 expression could ameliorate fibrosis(7-9). Although Takumi Yoshida et al. demonstrated that renal IRI and oxidative stress during this period significantly enhanced ATF3 expression in the acute phase(10), there is a lack of research in the field of severe IRI on interstitial fibrosis of transplanted kidneys in the chronic phase. Notably, ATF3 upregulation restricts the activation of Nrf2 signaling pathway, thus aggravating ferroptosis(11), which may be due to the fact that ATF3-Nrf2 heterodimer formed on the promoter of Nrf2 target gene ARE directly inhibits the antioxidant stress ability of Nrf2(12). In addition, renal tubular epithelial cells (RTECs) are considered to be the most sensitive cells to ferroptosis in the kidney, and are usually the most serious parenchymal cells of IRI(13,14). Inhibition of ferroptosis in RTECs is helpful to alleviate RIF(15), so it’s suspected that ATF3 may promote ferroptosis in RTECs by inhibiting Nrf2 signaling pathway in IRI-related RIF of transplanted kidney. Exosomes is an important regulator of transplanted kidney and immune system, and promote the repair and fibrosis of kidney tissue suffering from IRI(16). Intriguingly, Dai EY et al. proved for the first time in 2020 that there is a connection between ferroptotic cells and macrophages, that is, the exosomes released by ferroptotic cancer cells carry KRAS, which led to M2 macrophages polarization(17). Subsequently, in 2022, Qiying Chen et al. further proved that exosomes derived from ferroptotic cardiomyocytes affected M1 macrophages polarization, contributing to the pathological progression of myocardial infarction(18). Although the exosomes secreted by RTECs can promote RIF following IRI(19), it is still unknown whether exosomes derived from ferroptotic RTECs can induce macrophage polarization and the internal mechanism. Hence, this study aimed to investigate that ATF3 promoted ferroptosis in RTECs by inhibiting Nrf2 pathway, and the exosomes derived from ferroptotic RTECs induced M1/M2 ratio imbalance, offering a potential therapeutic target for decelerating the progression of renal IRI towards RIF.