NEK7 mediates ESRD-associated endothelial injury by activating the NLRP3 inflammasome.

Cardiovascular disease (CVD) is reported to closely associate with the high mortality in patients with end-stage renal disease (ESRD), and endothelial damage induced by accumulated uremic toxins (mostly studied indoxyl sulfate [IS]) is the key pathological process, whose pathogenesis and therapeutic strategies remain incompletely understood. NIMA-related kinase 7 (NEK7) has been recognized as a novel mediator for NLRP3 inflammasome activation, which plays a crucial part in causing vascular endothelial injury. Here, we explored the potential functions and fundamental mechanisms of NEK7-mediated NLRP3 inflammasome activation in IS-induced endothelial injury. Expression of the NLRP3 inflammasome and its activation were markedly increased in IS-administered endothelium both in vivo and in vitro. Silencing NEK7, NLRP3, or caspase 1 significantly inhibited NLRP3 inflammasome activation, thereby alleviating IS-induced endothelial injury, as indicated by reduced inflammation and apoptosis in mouse arterial endothelial cells (MAECs). Furthermore, impaired endothelium in the aortas of both five-sixths nephrectomy mice and IS-injected mice with activated NLRP3 inflammasome, was either restored when conditional knockdown of NEK7 in endothelial cells or amplified upon NEK7 overexpression via hydrodynamic tail vein injection. Together, we validate that NEK7 promotes IS-induced endothelial injury by activating the NLRP3 inflammasome, which not only sheds lights on the underlying mechanisms of IS-mediated endothelial injury in ESRD, but also provides potential pharmacological target for the therapy of ESRD-related CVD.