PUBLICATION
Effects of Proximal Tubule Shortening on Protein Excretion in a Lowe Syndrome Model
- Authors
- Gliozzi, M.L., Espiritu, E.B., Shipman, K.E., Rbaibi, Y., Long, K.R., Roy, N., Duncan, A.W., Lazzara, M.J., Hukriede, N.A., Baty, C.J., Weisz, O.A.
- ID
- ZDB-PUB-191106-4
- Date
- 2019
- Source
- Journal of the American Society of Nephrology : JASN 31(1): 67-83 (Journal)
- Registered Authors
- Keywords
- Fanconi syndrome, OCRL, megalin, mitosis, phosphatidylinositol 4,5-bisphosphate, proximal tubule
- MeSH Terms
-
- Cell Line
- Humans
- Kidney Tubules, Proximal/physiology*
- Models, Biological
- Mutation
- Oculocerebrorenal Syndrome/genetics
- Oculocerebrorenal Syndrome/metabolism*
- Phosphoric Monoester Hydrolases/genetics
- Proteins/metabolism*
- PubMed
- 31676724 Full text @ J. Am. Soc. Nephrol.
Citation
Gliozzi, M.L., Espiritu, E.B., Shipman, K.E., Rbaibi, Y., Long, K.R., Roy, N., Duncan, A.W., Lazzara, M.J., Hukriede, N.A., Baty, C.J., Weisz, O.A. (2019) Effects of Proximal Tubule Shortening on Protein Excretion in a Lowe Syndrome Model. Journal of the American Society of Nephrology : JASN. 31(1):67-83.
Abstract
Background Lowe syndrome (LS) is an X-linked recessive disorder caused by mutations in OCRL, which encodes the enzyme OCRL. Symptoms of LS include proximal tubule (PT) dysfunction typically characterized by low molecular weight proteinuria, renal tubular acidosis (RTA), aminoaciduria, and hypercalciuria. How mutant OCRL causes these symptoms isn't clear.
Methods We examined the effect of deleting OCRL on endocytic traffic and cell division in newly created human PT CRISPR/Cas9 OCRL knockout cells, multiple PT cell lines treated with OCRL-targeting siRNA, and in orcl-mutant zebrafish.
Results OCRL-depleted human cells proliferated more slowly and about 10% of them were multinucleated compared with fewer than 2% of matched control cells. Heterologous expression of wild-type, but not phosphatase-deficient, OCRL prevented the accumulation of multinucleated cells after acute knockdown of OCRL but could not rescue the phenotype in stably edited knockout cell lines. Mathematic modeling confirmed that reduced PT length can account for the urinary excretion profile in LS. Both ocrl mutant zebrafish and zebrafish injected with ocrl morpholino showed truncated expression of megalin along the pronephric kidney, consistent with a shortened S1 segment.
Conclusions Our data suggest a unifying model to explain how loss of OCRL results in tubular proteinuria as well as the other commonly observed renal manifestations of LS. We hypothesize that defective cell division during kidney development and/or repair compromises PT length and impairs kidney function in LS patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping