PUBLICATION
Oxysterol-binding protein like 7 deficiency leads to ER stress mediated apoptosis in podocytes and proteinuria
- Authors
- Duara, J., Torres, M.F., Gurumani, M., Molina David, J., Njeim, R., Kim, J.J., Mitrofanova, A., Ge, M., Sloan, A.J., Müller-Deile, J., Schiffer, M., Merscher, S., Fornoni, A.
- ID
- ZDB-PUB-240704-15
- Date
- 2024
- Source
- American journal of physiology. Renal physiology 327(3): F340-F350 (Journal)
- Registered Authors
- Keywords
- chronic kidney disease, er stress, glomerular disease, podocyte, proteinuria
- MeSH Terms
-
- Animals
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Podocytes*/metabolism
- Podocytes*/pathology
- Male
- Receptors, Steroid*/deficiency
- Receptors, Steroid*/genetics
- Receptors, Steroid*/metabolism
- Apoptosis*
- Autophagy
- Zebrafish
- Disease Models, Animal
- Endoplasmic Reticulum Stress*
- Proteinuria*/genetics
- Proteinuria*/metabolism
- Proteinuria*/pathology
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- PubMed
- 38961844 Full text @ Am. J. Physiol. Renal Physiol.
Citation
Duara, J., Torres, M.F., Gurumani, M., Molina David, J., Njeim, R., Kim, J.J., Mitrofanova, A., Ge, M., Sloan, A.J., Müller-Deile, J., Schiffer, M., Merscher, S., Fornoni, A. (2024) Oxysterol-binding protein like 7 deficiency leads to ER stress mediated apoptosis in podocytes and proteinuria. American journal of physiology. Renal physiology. 327(3):F340-F350.
Abstract
Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein like 7 (OSBPL7) modulates the expression and function of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Employing mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. While as expected the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7-deficiency related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7-deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study shed new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthen the role of OSBPL7 as a novel therapeutic target.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping