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other·nephrology, preclinical research, biomedical research, cardiology, endocrinology·PMC10451761

Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency

Antioxidants · 9 authors, 3 centres

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TL;DR

This preclinical study used serum and isolated lipoproteins from human LCAT-deficient carriers to treat cultured renal cells (podocytes and tubular cells). It found that the abnormal lipoproteins, specifically lipoprotein X and high-density lipoprotein, triggered oxidative stress and cell apoptosis in the renal cells.

Full summary

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The study used an in vitro model to investigate the nephrotoxic mechanisms of lipoproteins from familial LCAT deficiency (FLD) patients. Serum and lipoprotein fractions (lipoprotein X and high-density lipoprotein) isolated from homozygous FLD carriers were applied to cultured human podocytes and tubular cells. The primary outcomes measured were oxidative stress (reactive oxygen species production) and apoptosis. Results showed that both lipoprotein X and high-density lipoprotein from FLD carriers induced oxidative stress and apoptosis in renal cells. This toxicity was linked to lipoprotein enrichment in unesterified cholesterol and ceramides. The study concludes that these abnormal lipoproteins are direct mediators of nephrotoxicity in FLD. Key limitations are the small sample size due to disease rarity and that findings are based on ex vivo and in vitro experiments, requiring further in vivo validation.

STUDY TYPE

other

SPECIALTY

nephrology

SUMMARISED BY

AI pipeline

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100% · A

ORIGINAL PAPER

PMC10451761

Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency

Antioxidants

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ABSTRACT

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the LCAT gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lipoprotein (HDL) cholesterol and the accumulation of lipoprotein X (LpX). Renal failure is the major cause of morbidity and mortality in FLD patients; the pathogenesis of renal disease is only partly understood, but abnormalities in the lipoprotein profile could play a role in disease onset and progression. Serum and lipoprotein fractions from LCAT deficient carriers and controls were tested for renal toxicity on podocytes and tubular cells, and the underlying mechanisms were investigated at the cellular level. Both LpX and HDL from LCAT-deficient carriers triggered oxidative stress in renal cells, which culminated in cell apoptosis. These effects are partly explained by lipoprotein enrichment in unesterified cholesterol and ceramides, especially in the HDL fraction. Thus, alterations in lipoprotein composition could explain some of the nephrotoxic effects of LCAT deficient lipoproteins on podocytes and tubular cells.

CITATION EXPORT

Monica Gomaraschi, Marta Turri, Arianna Strazzella et al.. Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency. Antioxidants. (2023). https://doi.org/10.3390/antiox12081498

AUTHORS

9 · 3 CENTRES

Monica Gomaraschi, Marta Turri, Arianna Strazzella, Marie Lhomme, Chiara Pavanello, Wilfried Le Goff, Anatol Kontush, Laura Calabresi, Alice Ossoli

1Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy; [email protected] (M.G.); [email protected] (M.T.); [email protected] (C.P.); [email protected] (A.O.)
2Foundation for Innovation in Cardiometabolism and Nutrition (ANR-10-IAHU-05), IHU ICAN (ICAN OMICS and ICAN I/O), 75013 Paris, France; [email protected]
3National Institute for Health and Medical Research (INSERM), UMRS 1166 ICAN, Faculty of Medicine Pitié-Salpêtrière, Sorbonne University, 75013 Paris, France; [email protected] (W.L.G.); [email protected] (A.K.)

EDITOR / REVIEWER

Claus Jacob