TGF-Β1 and CASPASE-3 are involved in Fabry nephropathy

BONDAR, C.; MUCCI, J.; BOLLA, MARÍA DE LOS ÁNGELES; QUIETO, PEDRO; PISANI, A; FERIOZZI, S; NEUMAN, PABLO; ROZENFELD, P.

Congreso; XII Congreso SLEIMPN; 2022

INTRODUCTION: The kidney is one of the main target organs in Fabry disease, a lysosomal X-linkeddisorder. Renal involvement is characterized by proteinuria and progressive chronic kidney disease.Pathogenic mechanisms were not fully described. Lysosomal Gb3 deposition occurs followed by complexpathological pathways resulting in renal sclerosis/fibrosis. TGF-β1 is an important cytokine involved inkidney fibrosis and can also mediate apoptosis. Our previous results showed positive staining for TGF-β1in tubular epithelial cells in biopsies from Fabry patients. The apoptotic marker active-caspase-3 was alsoobserved in tubular cells. AIMS: To quantify TGF-β1 and active caspase-3 expression by tubular cells inkidney biopsies from Fabry naïve patients and non-Fabry individuals, and to analyze possible correlationsamong these markers and clinical or histopathological parameters. METHODS: Fifteen renal biopsiesfrom naïve Fabry patients and 5 from non-Fabry individuals were included. Immunofluorescence stainingfor TGF-β1 and active-caspase-3 was performed. Fluorescence intensities were quantified using Image-Jsoftware. These markers were compared among patients according to sex, age, classical or late-onsetFabry disease, interstitial fibrosis and infiltration scores, proteinuria and glomerular filtration rate. Theprocedures followed were approved by the Ethical Committee of Framingham (La Plata,Argentina). RESULTS: TGF-β1 tubular expression was increased in Fabry classic patient´ specimens ascompared to late-onset ones. Levels were independent of age or sex. Active-caspase-3 expressionpresented a similar tendency although without statistical difference. There was no correlation betweenTGF-β1 and active-caspase-3 levels. Caspase-3 was elevated in patients presenting inflammatoryinfiltration. This marker was also shown to correlate with proteinuria and glomerular filtration rate. Nocorrelations were observed for TGF-β1 and histological/clinical parameters. CONCLUSIONS: TGF-β1 ishighly expressed by tubular cells in kidney biopsies from Fabry naïve patients. TGF-β1 expression ishigher in the classic variant of the disease showing that this cytokine plays a key role in thepathogenesis. However, it showed no correlation with active-caspase-3. The apoptotic marker showed tocorrelate with proteinuria (positively) and glomerular filtration rate (negatively), suggesting that tubularcell death is a clear component of Fabry nephropathy and it could be secondary to the increment inproteinuria levels rather than a direct effect of TGF-β1.