NGAL drives cardiac dysfunction and fibrosis in rats with chronic kidney disease

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Abstract
Background: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular (CV) complications. Neutrophil gelatinase-associated lipocalin (NGAL) is a well established marker of kidney injury, but recent evidence suggests that NGAL might also play an active in the progression of the cardiorenal syndrome. Methods: CKD was induced in rats via 5/6 nephrectomy in wild-type (WT) and Ngal-knockout (KO) rats. Cardiorenal functions were assessed three months after subtotal nephrectomy or sham operation. Cardiac fibroblasts (CFs) were incubated with or without recombinant Ngal and galectin-3 (Gal-3). Results: Cardiac function, including diastolic hemodynamics and perfusion, was less impaired in CKD Ngal KO than in CKD WT. Cardiac fibrosis was more severe in CKD WT than sham, but was blunted in CKD Ngal KO rats. Levels of Gal-3, collagen I, MCP-1 and IL-6 were elevated in cardiac fibroblasts incubated with recombinant Ngal. A similar pattern was observed in cells treated with recombinant Gal-3. Both Ngal and Gal-3 induced activation of the Tlr4-Myd88 pathway. Using Gal-3 or Tlr4 inhibitors, we showed that Gal-3 contributes to Ngal-induced cardiac fibrosis and inflammation by activating the Tlr4-Myd88 pathway. In patients with heart failure with preserved ejection fraction (HFpEF) (MEDIA-DHF and BIOSTAT-CHF cohorts), elevated levels of NGAL and Gal-3 were associated with pulmonary artery systolic pressure, a marker of advanced diastolic dysfunction and adverse clinical outcomes, particularly among patients with impaired renal function. Conclusion: In non-diabetic CKD rats, Ngal was involved in the progression of diastolic dysfunction via a Gal-3/Tlr4-dependent pathway increasing inflammation and fibrosis.

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