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Kidney Week

Abstract: PO2514

Oxysterol-Binding Protein Like 7 in CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Pressly, Jeffrey D., University of Miami School of Medicine, Miami, Florida, United States
  • Varona Santos, Javier T., University of Miami School of Medicine, Miami, Florida, United States
  • Ge, Mengyuan, University of Miami School of Medicine, Miami, Florida, United States
  • Merscher, Sandra M., University of Miami School of Medicine, Miami, Florida, United States
  • Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
Background

ATP-binding cassette transporter A1 (ABCA1)-mediated, cholesterol ester-induced podocyte injury plays a major role in the progression of glomerular disease and pharmacological inducers of ABCA1 (ABCA1i) are sufficient to partially rescue glomerular injury in proteinuric mice. Interestingly, these ABCA1i’s compete specifically with oxysterol binding to oxysterol-binding protein (OSBP) like 7 (OSBPL7), a member of a group of lipid-binding proteins involved in lipid transport between intracellular membranes. OSBPs are implicated in cholesterol transfer from the endoplasmic reticulum (ER) to the Golgi, in cholesterol efflux and in the regulation of ABCA1 expression. However, if OSBPL7 is expressed in the kidney and if it is involved in the preservation of ER function has not been explored.

Methods

In this study, we utilized podocytes and tissues obtained from wildtype and Col4a3-/- mice, an experimental model of CKD. siOSBPL7 Podocytes and HEK293 cell lines were established using siRNA yielding these cells deficient in OSBPL7. HEK cells do not express ABCA1 making them a valuable tool to study the ABCA1 independent effects of OSBPL7. OSBPL7 levels were determined from kidney cortex and isolated podocytes from WT and Col4a3-/- mice by western blot, immunohistochemistry, and RT-PCR. siOSBPL7 podocytes and HEK cells were analyzed for changes in ER stress markers, reactive oxygen species (ROS), cytotoxicity, and apoptosis.

Results

OSBPL7 is expressed in podocytes isolated from wildtype and Col4a3-/- mice, an experimental mouse model of chronic kidney disease. Western blot analysis revealed that OSBPL7 protein levels are reduced in kidney cortex of Col4a3-/- mice. siOSBPL7 podocytes and HEK293 cells show increased levels of ER stress, ROS, cytotoxicity, and apoptosis. Overexpression of OSBPL7 in Col4a3-/- podocytes lead to a reduction in apoptosis levels further indicating a beneficial role of OSBPL7 in podocytes.

Conclusion

This study represents the first time that OSBPL7 has been implicated in CKD. OSBPL7 deficiency in podocytes leads to ER stress and ultimately apoptosis suggesting that OSBPL7 levels are beneficial to podocyte function. Future studies will address the role of OSBPL7 in podocyte lipid trafficking in chronic kidney disease that may lead to the identification of novel therapeutic targets for the treatment of this prevalent and costly disease.

Funding

  • NIDDK Support