Calciprotein particle-induced cytotoxicity via lysosomal dysfunction and altered cholesterol distribution in renal epithelial HK-2 cells
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Scientific reports - 10(2020), 1 vom: 18. Nov., Seite 20125 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kunishige, Rina [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.04.2021 Date Revised 22.04.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-020-77308-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM317760327 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Calcifying Nanoparticles |2 NLM | |
| 650 | 7 | |a Calcium Phosphates |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a TFE3 protein, human |2 NLM | |
| 650 | 7 | |a TFEB protein, human |2 NLM | |
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| 700 | 1 | |a Tsubouchi, Asako |e verfasserin |4 aut | |
| 700 | 1 | |a Hanaoka, Kenjiro |e verfasserin |4 aut | |
| 700 | 1 | |a Miura, Yutaka |e verfasserin |4 aut | |
| 700 | 1 | |a Kurosu, Hiroshi |e verfasserin |4 aut | |
| 700 | 1 | |a Urano, Yasuteru |e verfasserin |4 aut | |
| 700 | 1 | |a Kuro-O, Makoto |e verfasserin |4 aut | |
| 700 | 1 | |a Murata, Masayuki |e verfasserin |4 aut | |
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