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Oxysterol-binding proteins (OSBPs) are known for their multifaceted roles, including the transfer of cholesterol between the endoplasmic reticulum and the Golgi apparatus, as well as regulating cholesterol efflux. Recent evidence suggests that the deficiency of one specific OSBP, OSBPL7, can attenuate autophagic processes in various cell types, thereby potentially influencing lipid trafficking and the functionality of podocytes—key cells involved in renal filtration. Given these preliminary observations, the current study aims to elucidate the role of OSBPL7 in the pathophysiology of chronic kidney disease (CKD). Specifically, we examine whether OSBPL7 deficiency contributes to CKD through mechanisms involving impaired autophagy and heightened endoplasmic reticulum stress.
In vitro murine CKD models (Col4a3-/- and db/db) and a complementary in vivo zebrafish model were used. Various analytical techniques such as transmission electron microscopy, western blot assays, and molecular diagnostic tools were employed to assess podocyte health indicators, ER stress markers, lipid content, and autophagic flux.
OSBPL7 deficiency correlated with increased podocyte injury in cultured podocytes. Col4a3-/- podocytes exhibited elevated apoptosis, which was significantly reduced when transfected with an OSBPL7 overexpressing plasmid, restoring apoptosis levels to those of Col4a3+/+ podocytes. The absence of the FFAT motif in OSBPL7 disrupted its protective impact, emphasizing ER binding. Elevated markers of ER stress and disrupted autophagy was demonstrated in siOSBPl7 podocytes compared to scOSBPl7 controls. ER stress was confirmed as the primary driver for OSBPl7 induced podocyte apoptosis. Furthermore, in zebrafish, OSBPL7 knockdown led to proteinuria and glomerular injury.
Our findings illuminate the pivotal role of OSBPL7 in podocyte integrity, highlighting its significance as a therapeutic target in CKD. Genetic reintroduction of OSBPL7 into the Col4a3-/- model notably ameliorated apoptosis, further affirming the protein's protective role. Our data link OSBPL7 deficiency to intracellular lipid accumulation in podocytes and proteinuria. While these results pave the way for a deeper understanding of OSBPL7's role in CKD, they also set the stage for future studies. Specifically, ensuing research will aim to elucidate the disease mechanisms underlying OSBPL7 deficiency in Alport syndrome, with a view to identify targeted therapeutic strategies for this and potentially other forms of CKD.