Nlrp3 Deficiency Alleviates Lipopolysaccharide-Induced Acute Kidney Injury via Suppressing Renal Inflammation and Ferroptosis in Mice

SIMPLE SUMMARY: Acute kidney injury is a common and severe group of clinical syndromes with numerous causes, including sepsis. The molecular mechanisms underlying sepsis-associated acute kidney injury development remain largely unknown, which explains the limitations of current clinical strategies. The NLRP3 inflammasome, the most widely researched inflammasome in the kidney, is crucial in the pathogenesis of sepsis and acute kidney injury. Herein, we sought to determine the expression of NLRP3 in patients with sepsis-associated acute kidney injury and investigate the significance and mechanisms of NLRP3 involvement. According to our data, patients with sepsis-associated acute kidney injury had upregulated NLRP3 expression in their kidneys. In addition, Nlrp3 deficiency strikingly attenuated sepsis-associated acute kidney injury. Mechanically, we found that Nlrp3 knockout reduced inflammation, reversed metabolic pathway changes, and decreased ferroptosis in the mouse kidneys. These findings indicate that Nlrp3 deficiency ameliorates sepsis-associated acute kidney injury via suppressing renal inflammation and ferroptosis and that substance metabolism modulation may be of importance for NLRP3 functioning. This sheds new light on the mechanisms of NLRP3 involvement in sepsis-associated acute kidney injury and provides further evidence for considering NLRP3 as a therapeutic target. ABSTRACT: The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is a vital component of many inflammatory responses. Here, we intended to investigate the involvement of NLRP3 in lipopolysaccharide (LPS)-induced sepsis-associated acute kidney injury (S-AKI) and explore its mechanisms. For the first time, we validated elevated NLRP3 expression in the renal tissues of S-AKI patients by immunohistochemistry analysis. Through LPS injection in both wild-type and Nlrp3(−/−) mice, a S-AKI model was developed. It was found that LPS-induced kidney injury, including an abnormal morphology in a histological examination, abnormal renal function in a laboratory examination, and an increase in the expression of AKI biomarkers, was dramatically reversed in Nlrp3-deficient mice. Nlrp3 deletion alleviated renal inflammation, as evidenced by the suppression of the expression of pro-inflammatory cytokines and chemokines. A combinative analysis of RNA sequencing and the FerrDb V2 database showed that Nlrp3 knockout regulated multiple metabolism pathways and ferroptosis in LPS-induced S-AKI. Further qPCR coupled with Prussian blue staining demonstrated that Nlrp3 knockout inhibited murine renal ferroptosis, indicating a novel mechanism involving S-AKI pathogenesis by NLRP3. Altogether, the aforementioned findings suggest that Nlrp3 deficiency alleviates LPS-induced S-AKI by reducing renal inflammation and ferroptosis. Our data highlight that NLRP3 is a potential therapeutic target for S-AKI.