Abstract Body: Background: Chronic kidney disease (CKD) patients are at high risk of cardiovascular complications. We have previously shown that Neutrophil Gelatinase-Associated Lipocalin (NGAL/lcn2), a kidney injury marker, is involved in aldosterone-induced cardiac remodeling and inflammation. This study aimed to better understand the role of NGAL in the progression of cardiorenal syndrome. Methods: CKD was induced in rats via 5/6 nephrectomy in wild-type and NGAL knockout (KO) rats. Cardiorenal functions were assessed three months after nephrectomy or sham operation. Cardiac fibroblasts were isolated from wild-type rats and incubated with or without 500 ng/ml of recombinant NGAL. Results: After three months, we did not observe clear modifications in kidney function or fibrosis in NGAL KO rats compared to wild-type rats. However, cardiac function, particularly diastolic hemodynamics and perfusion, was less impaired in CKD KO rats than in wild-type CKD rats. Moreover, cardiac fibrosis, which was increased in CKD compared to sham rats in the wild-type strain, was not increased in CKD KO rats compared to sham KO rats. In cardiac fibroblasts incubated with recombinant NGAL, we observed increased levels of galectin-3, IL-6, collagen III, and MCP-1. We observed a similar pattern in cells treated with recombinant galectin-3, with increased IL-6 and CCL2 gene expression. This expression was blunted by co-treatment with both galectin-3 and galectin-3 inhibitor Modified Citrus Pectin (MCP), suggesting a role for galectin-3 in mediating the cardiac consequences of NGAL on fibrosis and inflammation. Conclusion: NGAL is involved in the progression of cardiac failure, particularly diastolic dysfunction, via a galectin-3-dependent pathway leading to increased inflammation and fibrosis.