Nitrite Protects Against Cardiac Surgery-Associated AKI via Inflammation Suppression: Insights from a Rat CPB Model

Background: Cardiac surgery-associated acute kidney injury (CS-AKI) is reported in 20-30% of patients undergoing cardiac surgery and, leading to poor outcomes and increased healthcare costs. Because the pathophysiology of CS-AKI is complex and has not been fully elucidated, no effective preventive and interventional strategy has been reported. Nitrite, a nitric oxide (NO) donor under hypoxic conditions, has shown to exert organ-protective effects in various kind of preclinical models, however, its efficacy in CS-AKI remains unclear. Objectives: This study aimed to generate a rat cardiopulmonary bypass (CPB) model to induce AKI, identify key molecular pathways involved in its pathophysiology, and evaluate the renoprotective effects of nitrite. Methods: A CPB model was established using rats and AKI was confirmed through molecular and histological analysis. RNA-seq was performed to identify differentially expressed genes and enriched pathway. Nitrite (2 mg/kg) was intravenously administered prior to CPB, and its effects on kidney injury markers and inflammation-related pathways were evaluated. Results: AKI was successfully produced in our rat CPB model, as evidenced by increased KIM-1 and NGAL expression and renal histological damage. RNA-seq revealed significant activation of multiple inflammation-related pathways, including TNF and NF?B signaling pathway. Nitrite administration significantly reduced KIM-1 and NGAL expression and suppressed these pathways associated with development of AKI. Conclusion: This study underscores the role of inflammation in CS-AKI pathophysiology and demonstrates the renoprotective potential of nitrite. These findings provide a foundation for further investigations into nitrite's mechanisms and its potential clinical application in cardiac surgery. Overall design: RNA-seq profiling of acute kidney injury after CPB and the renoprotective effects of nitrite using a rat CPB model