Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-32389-z
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Funding
- Fonds pour la Recherche Scientifique (F.R.S-FNRS, Belgium), Universite catholique de Louvain (Actions de Recherche concertees
- University of Liege (Fonds Speciaux a la Recherche, Fonds Leon Fredericq)
- F.R.S.-FNRS (Research Credit 2013)
- F.R.S.-FNRS (Research Credit 2016)
- MRC [G0700755]
- BBSRC [BB/I007806/1, BB/M013278/1]
- National Lottery
- Region bruxelloise
- Region wallonne
- Universite catholique de Louvain
- Duve Institute
- Fonds pour la formation a la Recherche dans l'Industrie et l'Agriculture (FRIA, Belgium)
- Cystinosis Research Foundation
- BBSRC [BB/I007806/2, BB/N013522/1, BB/M013278/1, BB/I007806/1] Funding Source: UKRI
- MRC [G0700755] Funding Source: UKRI
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Kidney proximal tubular cells (PTCs) are highly specialized for ultrafiltrate reabsorption and serve as paradigm of apical epithelial differentiation. Vps34/PI3-kinase type III (PI3KC3) regulates endosomal dynamics, macroautophagy and lysosomal function. However, its in vivo role in PTCs has not been evaluated. Conditional deletion of Vps34/PI3KC3 in PTCs by Pax8-Cre resulted in early (P7) PTC dysfunction, manifested by Fanconi-like syndrome, followed by kidney failure (P14) and death. By confocal microscopy, Vps34(Delta/Delta )PTCs showed preserved apico-basal specification (brush border, NHERF-1 versus Na+/K+-ATPase, ankyrin-G) but basal redistribution of late-endosomes/lysosomes (LAMP-1) and mis-localization to lysosomes of apical recycling endocytic receptors (megalin, cubilin) and apical non-recycling solute carriers (NaPi-Ila, SGLT-2). Defective endocytosis was confirmed by Texas-red-ova lbumin tracing and reduced albumin content. Disruption of Rab-11 and perinuclear galectin-3 compartments suggested mechanistic clues for defective receptor recycling and apical biosynthetic trafficking. p62-dependent autophagy was triggered yet abortive (p62 co-localization with LC3 but not LAMP-1) and PTCs became vacuolated. Impaired lysosomal positioning and blocked autophagy are known causes of cell stress. Thus, early trafficking defects show that Vps34 is a key in vivo component of molecular machineries governing apical vesicular trafficking, thus absorptive function in PTCs. Functional defects underline the essential role ofVps34 for PTC homeostasis and kidney survival.
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