Oxysterol-binding protein-like 7 deficiency leads to ER stress-mediated apoptosis in podocytes and proteinuria
Duara J, Torres M, Gurumani M, David JM, Njeim R, Kim JJ, Mitrofanova A, Ge M, Sloan A, Müller-Deile J, Schiffer M, Merscher S, Fornoni A (2024)
Publication Type: Journal article
Publication year: 2024
Journal
Book Volume: 327
Pages Range: F340-F350
Journal Issue: 3
DOI: 10.1152/ajprenal.00319.2023
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. Using 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. Although 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 sheds new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthens the role of OSBPL7 as a novel therapeutic target.
Authors with CRIS profile
Janina Müller-Deile
Department of Medicine 4 – Nephrology and Hypertension
Mario Schiffer
Lehrstuhl für Innere Medizin IV
Additional Organisation(s)
Involved external institutions
United States (USA) (US)How to cite
APA:
Duara, J., Torres, M., Gurumani, M., David, J.M., Njeim, R., Kim, J.J.,... 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. https://doi.org/10.1152/ajprenal.00319.2023
MLA:
Duara, Joanne, et al. "Oxysterol-binding protein-like 7 deficiency leads to ER stress-mediated apoptosis in podocytes and proteinuria." American Journal of Physiology-Renal Physiology 327.3 (2024): F340-F350.
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