Inhibition of endoplasmic reticulum stress signaling rescues cytotoxicity of human apolipoprotein-L1 risk variants in Drosophila.
Kidney Int
; 101(6): 1216-1231, 2022 06.
Artículo
en Inglés
| MEDLINE | ID: covidwho-1665244
ABSTRACT
Risk variants of the apolipoprotein-L1 (APOL1) gene are associated with severe kidney disease, putting homozygous carriers at risk. Since APOL1 lacks orthologs in all major model organisms, a wide range of mechanisms frequently in conflict have been described for APOL1-associated nephropathies. The genetic toolkit in Drosophila allows unique in vivo insights into disrupted cellular homeostasis. To perform a mechanistic analysis, we expressed human APOL1 control and gain-of-function kidney risk variants in the podocyte-like garland cells of Drosophila nephrocytes and a wing precursor tissue. Expression of APOL1 risk variants was found to elevate endocytic function of garland cell nephrocytes that simultaneously showed early signs of cell death. Wild-type APOL1 had a significantly milder effect, while a control transgene with deletion of the short BH3 domain showed no overt phenotype. Nephrocyte endo-lysosomal function and slit diaphragm architecture remained unaffected by APOL1 risk variants, but endoplasmic reticulum (ER) swelling, chaperone induction, and expression of the reporter Xbp1-EGFP suggested an ER stress response. Pharmacological inhibition of ER stress diminished APOL1-mediated cell death and direct ER stress induction enhanced nephrocyte endocytic function similar to expression of APOL1 risk variants. We confirmed APOL1-dependent ER stress in the Drosophila wing precursor where silencing the IRE1-dependent branch of ER stress signaling by inhibition with Xbp1-RNAi abrogated cell death, representing the first rescue of APOL1-associated cytotoxicity in vivo. Thus, we uncovered ER stress as an essential consequence of APOL1 risk variant expression in vivo in Drosophila, suggesting a central role of this pathway in the pathogenesis of APOL1-associated nephropathies.
Palabras clave
Texto completo:
Disponible
Colección:
Bases de datos internacionales
Base de datos:
MEDLINE
Asunto principal:
Podocitos
/
Enfermedades Renales
Tipo de estudio:
Estudio pronóstico
Tópicos:
Variantes
Límite:
Animales
/
Humanos
Idioma:
Inglés
Revista:
Kidney Int
Año:
2022
Tipo del documento:
Artículo
País de afiliación:
J.kint.2021.12.031
Similares
MEDLINE
...
LILACS
LIS