Abstract: PO0924
Discovery of a Small-Molecule Drug for Treating Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: New Pathways and Therapies
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Al-Ali, Hassan, University of Miami School of Medicine, Miami, Florida, United States
- Varona Santos, Javier T., University of Miami School of Medicine, Miami, Florida, United States
- Sloan, Alexis J., 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
Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease and one of the fastest growing epidemics worldwide. Podocyte injury is a hallmark of DKD. As such, preventing podocyte injury is necessary for effectively treating DKD. Our prior studies demonstrated that the accumulation of lipid droplets (LDs) in podocytes is associated with increased susceptibility to apoptosis in the context of DKD. Conversely, reducing LD accumulation in podocytes prevented renal disease in a mouse model of DKD (BTBR ob/ob). Thus, compounds that reduce LD accumulation may protect podocytes from injury and prevent the progression of DKD. The goal of this study is to identify compounds that reduce LD accumulation in vivo and lead to the identification of therapeutic candidates for DKD.
Methods
Advances in high throughput synthetic chemistry have enabled the design of combinatorial libraries for efficient screening and identification of novel bioactive compounds. The approach is particularly powerful when combined with a phenotypic screening assay that recapitulates disease biology. We have developed a high content screening assay to quantify LD accumulation in human podocytes in response to stress stimuli. The assay is highly suitable for screening with a Z factor consistently > 0.5.
Results
We performed a pilot screen using 100 compound mixtures, each containing thousands of compounds, obtained from the Torrey Pines Institute for Molecular Studies (TPIMS). We identified one compound mixture (2275) that consistently reduces LD accumulation in a dose-dependent manner. 2275 significantly reduces LD accumulation induced by TNF, a pro-inflammatory cytokine associated with DKD, and induced by sera from patients with DKD. The TPIMS hit deconvolution method will be used to identify the active compound(s) within the 2275 mixture.
Conclusion
We identified compounds that significantly reduce LD accumulation in cultured human podocytes in response to stress stimuli, including sera from DKD patients. Further studies to deconvolve and validate those compounds, and test them in an animal model of DKD, are underway.