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Kidney Week

Abstract: PO0643

Novel Small Molecule Inducers of ABCA1-Dependent Cholesterol Efflux Preserve Renal Function in Mouse Models of FSGS and Alport Syndrome

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Varona Santos, Javier T., University of Miami, Katz Family Division of Nephrology and Hypertension, Miami, Florida, United States
  • Wright, Matthew B., Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • Kemmer, Christian, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • Maugeais, Cyrille, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • Carralot, Jean-Philippe, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • Roever, Stephan, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • Molina David, Judith T., University of Miami, Katz Family Division of Nephrology and Hypertension, Miami, Florida, United States
  • Ducasa, Gloria Michelle, University of Miami, Katz Family Division of Nephrology and Hypertension, Miami, Florida, United States
  • Mitrofanova, Alla, University of Miami, Katz Family Division of Nephrology and Hypertension, Miami, Florida, United States
  • Sloan, Alexis J., University of Miami, Katz Family Division of Nephrology and Hypertension, Miami, Florida, United States
  • Pressly, Jeffrey D., University of Miami, Katz Family Division of Nephrology and Hypertension, Miami, Florida, United States
  • Pedigo, Christopher, University of Miami, Katz Family Division of Nephrology and Hypertension, Miami, Florida, United States
  • Barisoni, Laura, University of Miami Department of Pathology, Miller School of Medicine, Miami, Florida, United States
  • Mendez, Armando, University of Miami, Miller School of Medicine, Diabetes Research Institute, Miami, Florida, United States
  • Sgrignani, Jacopo, Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
  • Cavalli, Andrea, Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
  • Merscher, Sandra M., Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • Prunotto, Marco, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • Fornoni, Alessia, University of Miami, Katz Family Division of Nephrology and Hypertension, Miami, Florida, United States
Background

Pathological accumulation of cholesterol in podocytes is associated with the progression of kidney disease. Depletion of podocyte cholesterol by non-specific means, with agents such as cyclodextrin, or by specific upregulation of ABCA1- mediated cholesterol efflux, have shown promise in renal disease models, but have not progressed in clinical development.

Methods

The effects of novel compounds (Cpds A and G) that induce ABCA1-mediated cholesterol efflux were evaluated in comparison to LXR agonists in differentiated human podocytes in vitro. In vivo efficacy studies of Cpds A & G were conducted in mouse models of proteinuric kidney disease (Adriamycin-induced nephropathy and Alport Syndrome).

Results

ABCA1-mediated cholesterol efflux was significantly increased in podocytes by all agents. While an LXR agonist resulted in accumulation of ABCA1 at the plasma membrane, it also induced significant accumulation in microsomal fractions. In contrast, Cpds A & G induced the redistribution of ABCA1 from intracellular sites to the plasma membrane. In ADR challenged mice, Cpd A and Cpd G reduced ACR by 8 and 30-fold, respectively, compared to controls. In Col4A3 knockout mice, Cpd G significantly reduced ACR, serum creatinine and blood urea nitrogen, as well as prevented weight loss and mortality vs. control mice. We found that increased accumulation of cholesterol esters in the kidney cortex of ADR challenged mice strongly correlated with albuminuria. In both the FSGS and Alport models, Cpd G significantly reduced lipid droplet formation and cholesterol ester content in kidney cortex.

Conclusion

In summary, our studies describe the effects of novel small molecule drugs in renal disease models that induce ABCA1-mediated cholesterol efflux independently of LXR. This may represent a promising new therapeutic strategy for the treatment of kidney diseases and disorders of cellular cholesterol homeostasis.

Funding

  • NIDDK Support