TGF-Β1 AND CASPASE-3 ARE INVOLVED IN FABRY NEPHROPATHY

BONDAR, C.; MUCCI, J.M.; BOLLA, MA; QUIETO, P; PISANI, A; FERIOZZI, S; NEUMANN, P; ROZENFELD, P.A.

Punta Cana

Congreso; Congreso Latinoamericano de Errores Innatos del Metabolismo y Pesquiza Neonatal; 2022

INTRODUCTION: The kidney is one of the main target organs in Fabry disease, a lysosomal X-linked disorder. Renal involvement is characterized by proteinuria and progressive chronic kidney disease. Pathogenic mechanisms were not fully described. Lysosomal Gb3 deposition occurs followed by complex pathological pathways resulting in renal sclerosis/fibrosis. TGF-β1 is an important cytokine involved in kidney fibrosis and can also mediate apoptosis. Our previous results showed positive staining for TGF-β1 in tubular epithelial cells in biopsies from Fabry patients. The apoptotic marker active-caspase-3 was also observed in tubular cells. AIMS: To quantify TGF-β1 and active caspase-3 expression by tubular cells in kidney biopsies from Fabry naïve patients and non-Fabry individuals, and to analyze possible correlations among these markers and clinical or histopathological parameters. METHODS: Fifteen renal biopsies from naïve Fabry patients and 5 from non-Fabry individuals were included. Immunofluorescence staining for TGF-β1 and active-caspase-3 was performed. Fluorescence intensities were quantified using Image-J software. These markers were compared among patients according to sex, age, classical or late-onset Fabry disease, interstitial fibrosis and infiltration scores, proteinuria and glomerular filtration rate. The procedures followed were approved by the Ethical Committee of Framingham (La Plata, Argentina). RESULTS: TGF-β1 tubular expression was increased in Fabry classic patient´ specimens as compared to late-onset ones. Levels were independent of age or sex. Active-caspase-3 expression presented a similar tendency although without statistical difference. There was no correlation between TGF-β1 and active-caspase-3 levels. Caspase-3 was elevated in patients presenting inflammatory infiltration. This marker was also shown to correlate with proteinuria and glomerular filtration rate. No correlations were observed for TGF-β1 and histological/clinical parameters. CONCLUSIONS: TGF-β1 is highly expressed by tubular cells in kidney biopsies from Fabry naïve patients. TGF-β1 expression is higher in the classic variant of the disease showing that this cytokine plays a key role in the pathogenesis. However, it showed no correlation with active-caspase-3. The apoptotic marker showed to correlate with proteinuria (positively) and glomerular filtration rate (negatively), suggesting that tubular cell death is a clear component of Fabry nephropathy and it could be secondary to the increment in proteinuria levels rather than a direct effect of TGF-β1.