#3457 Pathological role of Neuroaminidase-1 in nephrotic syndrome

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Abstract Background and Aims Infective disease are commonly associated with recurrence/occurence of nephrotic syndrome (NS). Neuroaminidase (NEU), an essential components of several microorganism, such as viruses, plays an essential role by removing sialic acids from the cell surface. Sialic acids play a crucial role in maintaining the polyanionic charge of the glomerular filtration barrier, which is essential for selective permeability. Pathologic glomerular hyposialylation, linked to podocyte effacement, has been associated with glomerulopathies in both humans and mouse models. Method We compared the Neuroaminidase-1 (NEU-1) activity in serum of patients with steroid-sensitive (n = 40) and steroid resistant NS (n = 10) with healthy controls (n = 30) and different glomerulonephritis (n = 15), including as Lupus and IgA nephropathies. Moreover, we performed mass spectrometry analysis of podocytes cell culture co-coltured with NEU-1. Results NEU-1 activity resulted significantly increased in patients with proteinuric NS, compared to Healthy subjects, non-proteinuric NS and other glomerulonephritis (Fig. 1A). In 15 NS patients with serum collected at two different time-points, with and without proteinuria in nephrotic range, NEU-1 activity resulted significantly higher in nephrotic condition than in remission (Fig. 1B). Moreover, more complicated forms of NS were associated wit an increased NEU-1 activity (Fig. 1C). Moreover, in vitro experiments suggested that when co-coltured with podocytes, NEU1 may affects the mRNA splicing, that may lead to dysfunctional or misfolded proteins, potentially compromising podocyte structure and function (Fig. 1D–F). Conclusion Our findings suggest that increased NEU-1 activity is strongly associated with proteinuric states in nephrotic syndrome, particularly in more severe and treatment-resistant forms. The dynamic variation of NEU-1 activity between nephrotic and remission phases further supports its role in disease pathophysiology. Moreover, in vitro evidence indicates that NEU-1 may influence podocyte integrity by altering mRNA splicing, potentially leading to structural and functional impairment. These results may support the rationale for administering N-acetylmannosamine (ManNAc), the uncharged precursor of sialic acid, in NS.

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