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Abstract: SA-PO441

Discovery and Development of a Therapeutic Lead Compound for Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Njeim, Rachel, University of Miami School of Medicine, Miami, Florida, United States
  • Donow, Haley M., Florida International University, Miami, Florida, United States
  • Molina David, Judith T., University of Miami School of Medicine, Miami, Florida, United States
  • Pressly, Jeffrey D., University of Miami School of Medicine, Miami, Florida, United States
  • Gye, Haley, University of Miami School of Medicine, Miami, Florida, United States
  • Merscher, Sandra M., University of Miami School of Medicine, Miami, Florida, United States
  • Giulianotti, Marc, Florida International University, Miami, Florida, United States
  • Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
  • Ali, Hassan, University of Miami School of Medicine, Miami, Florida, United States
Background

Diabetic kidney disease (DKD) is a leading cause of kidney failure worldwide. We previously demonstrated that the accumulation of lipid droplets (LDs) in podocytes leads to lipotoxicity and cell death in DKD. Drugs that lower circulating lipids do not halt DKD progression. However, directly reducing LD accumulation in podocytes was shown to slow disease progression in experimental DKD. We hypothesize that a drug that specifically targets LD accumulation in podocytes will be effective at halting or reversing DKD progression.

Methods

We developed a phenotypic assay using immortalized human podocytes and deployed it to screen a combinatorial library representing over 45 million unique compounds. We performed mechanistic analyses on hit compounds using transcriptomic, proteomic, and phenotypic techniques. We conducted medicinal chemistry to improve drug-like properties and tested one compound in a murine model of DKD.

Results

We identified and synthesized a series of novel compounds that effectively inhibit LD accumulation in podocytes and protect them from injury and cell death. RNAseq analysis revealed that these compounds significantly reduce the expression of genes that mediate tumor necrosis factor (TNF)-signaling, a pathway associated with LD accumulation and podocyte injury, and alter the expression of lysosome-associated membrane glycoprotein (LAMP), a regulator of autophagy. Mechanistic studies demonstrated that these compounds robustly activate autophagy/lipophagy, leading to a significant reduction in LD accumulation in podocytes. We tested one compound with improved drug-like properties in an experimental model of DKD, db/db mice, and found that it significantly prevented the progression of DKD, as evidenced by a reduction in albumin-to-creatinine ratios (ACR) and the reduced pathological renal damage associated with DKD.

Conclusion

Our screening assay successfully identified compounds that protect podocytes from LD accumulation by inducing lipophagy. We developed a lead candidate from our initial hit series that demonstrates remarkable efficacy in preventing DKD progression in vivo. We are continuing lead optimization efforts toward generating a clinical candidate for testing in a clinical trial.

Funding

  • NIDDK Support