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Mechanism and restoration strategy of lysosomal abnormalities induced by urinary protein overload in proximal tubule epithelial cells
Author(s) -
Li Xiaoyu,
Zou Ting,
Wang Shujun,
Wu Hongluan,
Wu Man,
Liu Zejian,
Liu Huafeng
Publication year - 2021
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.297
Subject(s) - biology , mechanism (biology) , microbiology and biotechnology , urinary system , proximal tubule , anatomy , endocrinology , kidney , philosophy , epistemology
Background Persistent elevated concentrations of urinary protein can destroy proximal tubule epithelial cells (PTECs) by inducing lysosomal abnormalities, thereby aggravating PTEC damage and renal fibrosis. However, the specific mechanisms of these serial biochemical events and methods for treating or preventing PTEC damage upon proteinuria need further investigation. Results In this study, electron microscopy and dual‐labeled immunofluorescence analysis for identifying lysosome type revealed inadequate primary lysosome biogenesis and secondary lysosome accumulation in the PTECs of patients with minimal change nephrotic syndrome or membranous nephropathy who suffered from proteinuria. In vitro studies on HK‐2 cells indicated that this abnormality was associated with decreased expression of transcription factor EB (TFEB). In contrast, TFEB overexpressing HK‐2 cells under urinary protein overload exhibited significantly reduced accumulation of secondary lysosomes and increased proportion and quantity of primary lysosomes as indicated by dual‐labeled immunofluorescence. Further, these cells could upregulate lysosomal degradation functions, as determined using Cathepsin L activity assays and flow cytometry for dye quenched‐albumin. Conclusions These results indicate that abnormal TFEB expression is a key mechanism of lysosomal dyshomeostasis caused by protein overload in PTECs. TFEB is thus a potential therapeutic target for the treatment of urinary protein‐related kidney disease.

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