Acute kidney injury (AKI) is a serious condition with high mortality. The most common cause is kidney ischemia/reperfusion (IR) injury, which is thought to be closely related to pyroptosis. Disulfiram is a well-known alcohol abuse drug, and recent studies have shown its ability to mitigate pyroptosis in mouse macrophages. This study investigated whether disulfiram could improve IR-induced AKI and elucidated the possible molecular mechanism. We generated an IR model in mouse kidneys and a hypoxia/reoxygenation (HR) injury model with murine tubular epithelial cells (MTECs). The results showed that IR caused renal dysfunction in mice and triggered pyroptosis in renal tubular epithelial cells, and disulfiram improved renal impairment after IR. The expression of proteins associated with the classical pyroptosis pathway (Nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3), apoptosis-related specific protein (ASC), caspase-1, N-GSDMD) and nonclassical pyroptosis pathway (caspase-11, N-GSDMD) were upregulated after IR. Disulfiram blocked the upregulation of nonclassical but not all classical pyroptosis pathway proteins (NLRP3 and ASC), suggesting that disulfiram might reduce pyroptosis by inhibiting the caspase-11-GSDMD pathway. In vitro, HR increased intracellular ROS levels, the positive rate of PI staining and LDH levels in MTECs, all of which were reversed by disulfiram pretreatment. Furthermore, we performed a computer simulation of the TIR domain of TLR4 using homology modeling and identified a small molecular binding energy between disulfiram and the TIR domain. We concluded that disulfiram might inhibit pyroptosis by antagonizing TLR4 and inhibiting the caspase-11-GSDMD pathway.

全球约有10%的成年人患有慢性肾脏疾病，不断攀升的肾脏疾病发病率对临床与公共卫生事业都是一个巨大的挑战。本文综述了近年来肾脏类器官的构建过程及其在肾脏疾病中的应用进展。类器官模型不仅在构建肾脏疾病模型中兼顾了动物模型和细胞培养的优点，还能对疾病进行治疗药物筛选和药物肾毒性检测。在未来，肾脏类器官也有望成为肾移植的供肾来源。

AIMS:Cisplatin is an anticancer agent marred by nephrotoxicity. Limiting this adverse effect may allow the use of higher doses to improve its efficacy. The Wnt/β-catenin signaling pathway plays a critical role in nephrogenesis and repair of renal diseases. BIO, a small molecule agonist of this pathway, exerted a protective effect in adriamycin nephropathy and promoted nephrogenesis. The aim of this study, therefore, was to investigate whether Wnt/β-catenin agonist BIO could protect against cisplatin-induced nephrotoxicity in vivo and in vitro, as well as its possible mechanism.MAIN METHODS:Male mice and human renal proximal tubular cells (HK-2) were subjected to cisplatin to study reno-protective effect of BIO. Renal function, cell viability, tubular apoptosis, production of reactive oxygen species (ROS) and proliferative level were analyzed respectively. Additionally, xenograft model was induced to investigate if BIO would impair the antitumor effect of cisplatin.KEY FINDINGS:Cisplatin increased serum creatinine levels and promoted histological renal injury as well as oxidative stress levels. Besides, renal apoptotic level and the expression of pro-apoptotic proteins, Bax/bcl-2 and cleaved-caspase3 included, in the kidney were increased. All these features were decreased by BIO, which also activated Wnt/β-catenin pathway in cisplatin-induced nephrotoxicity. Similarly, accompanied by the motivation of Wnt/β-catenin pathway, BIO exerted a positively protective effect on HK-2 challenged cisplatin. Last, the chemotherapeutic effects of cisplatin in xenograft mice of ovary tumor models and in lung cancer cells weren't compromised by BIO.SIGNIFICANCE:Wnt/β-catenin agonist BIO has the potential to prevent cisplatin nephrotoxicity without compromising its anti-proliferation efficacy.

Objective:To investigate the expression of Na +-dependent glucose transporter(SGLT) in human peritoneal mesothelial cells (HPMCs) and vascular endothelial cells in peritoneal tissues of peritoneal dialysis (PD) patients at different dialysis vintages, and to study the influence of high glucose treatment on the expression of SGLT1 and SGLT2 in primary HPMCs. Methods:According to the dialysis vintage, PD patients were divided into four groups: 0 year group, >0-2 years group, >2-4 years group and >4 years group. HE and Masson staining were used to observe the morphologic changes of peritoneal tissues in PD patients. Immunohistochemical staining was used to detect the expression of SGLT1 and SGLT2 in peritoneal HPMCs and vascular endothelial cells. The primary HPMCs were extracted from the peritoneal dialysis fluid, and treated with high-glucose or high-mannitol for 0 h, 12 h, 24 h, 48 h, 72 h and 96 h. Western blotting was used to investigate the SGLT1 and SGLT 2 expression in HPMCs. The cell viability was detected by using cell counting kit (CCK-8).Results:HE and Masson staining showed that the peritoneum of PD patients in 0 year group was smooth and continuous, with a flat layer of HPMCs. The number of HPMCs in>0-2 years group decreased compared with that in 0 year group. The HPMCs size increased in>2-4 years group, but the number decreased. The peritoneum of PD patients in>4 years group was significantly thickened and fibrotic, and HPMCs almost disappeared. Immunohistochemical staining showed that the expression of SGLT1 and SGLT2 in HPMCs gradually decreased with the increase of dialysis vintage ( P<0.05). The wall of peritoneal blood vessel became thicken, but the expression of SGLT1 and SGLT2 was not statistically different among four groups ( P>0.05). SGLT1 in primary HPMCs could be up-regulated (0 h, 12 h and 24 h), and then down-regulated (24 h, 48 h, 72 h, 96 h) with the treatment of 60 mmol/L glucose ( P=0.029); but there was no significant difference of SGLT2. Conclusion:High glucose and the increase of dialysis vintage can reduce the number and the viability of HPMCs, and decrease the expression of SGLT1 and SGLT2, but there was no significant influence on SGLT1 and SGLT2 in peritoneal vascular endothelial cells.