Calciprotein particle-induced cytotoxicity via lysosomal dysfunction and altered cholesterol distribution in renal epithelial HK-2 cells.

• 影响指数: 4.996
• 发表时间: 11 2020 18
• 来源期刊: Sci Rep
• DOI: 10.1038/s41598-020-77308-3
• PMID: 33208865
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 综合性期刊
• 作者列表: Kunishige R,Mizoguchi M,Tsubouchi A,Hanaoka K,Miura Y,Kurosu H,Urano Y,Kuro-O M,Murata M

Mesh: Autophagy / drug effects physiology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism; Calcifying Nanoparticles / pharmacokinetics toxicity; Calcium Phosphates / chemistry; Cell Line; Cell Membrane / drug effects metabolism; Cell Membrane Permeability / drug effects; Cholesterol / metabolism; Endocytosis; Epithelial Cells / drug effects metabolism pathology; Humans; Hydrogen-Ion Concentration; Kidney Tubules, Proximal / cytology; Lysosomes / metabolism pathology; Oxidative Stress / drug effects; Reactive Oxygen Species / metabolism

Abstract

Dietary phosphate overload induces chronic kidney disease (CKD), and calciprotein particles (CPPs), a form of nanoparticle comprising calcium phosphate and serum proteins, has been proposed to cause renal toxicity. However, the mechanism of CPP cytotoxicity in renal tubular cells is unknown. Here we show that in renal proximal tubular epithelial HK-2 cells, endocytosed CPPs accumulate in late endosomes/lysosomes (LELs) and increase their luminal pH by ~ 1.0 unit. This results in a decrease in lysosomal hydrolase activity and autophagic flux blockage without lysosomal rupture and reactive oxygen species generation. CPP treatment led to vulnerability to H2O2-induced oxidative stress and plasma membrane injury, probably because of autophagic flux blockage and decreased plasma membrane cholesterol, respectively. CPP-induced disruption of lysosomal homeostasis, autophagy flux and plasma membrane integrity might trigger a vicious cycle, leading to progressive nephron loss.