In vivo validation of novel compounds for treating diabetic kidney disease
Hassan Al-Ali   (Miami, FL)
Diabetic Kidney Disease (DKD) is the major cause of kidney failure in the US and one of the fastest growing epidemics worldwide. DKD-related healthcare expenditures are extraordinarily high, exceeding $25 billion in 2011 for the Medicare population alone. There are no FDA approved treatments for DKD, and its prevalence continues to rise despite increased use of glucose- and blood pressure-lowering medications. Loss of specialized kidney cells, called podocytes, underlies the development and progression of DKD. The main challenge for discovering effective therapies has been the lack of understanding of the mechanisms that cause podocyte loss, as well as the lack of screening systems that capture the complex pathophysiology of DKD. Our group has shown that podocytes of DKD patients accumulate lipids in the form of lipid droplets (LDs), which in turn render them susceptible to injury and cell death under diabetic conditions. Furthermore, we demonstrated that decreasing LD accumulation in podocytes prevents renal disease in a mouse model of DKD. Conversely, we showed that increasing LD accumulation in podocytes accelerates development and progression of DKD. We developed a robust phenotypic assay utilizing immortalized human podocytes and utilized it to identify compounds that reduce LD accumulation. We screened > 45 million unique molecules and identified a novel class of compounds that block LD accumulation in podocytes, thereby protecting them from lipotoxicity and cell death. These hits were validated by resynthesis and re-testing in a clinically relevant assay utilizing sera from patients with DKD. We performed synthetic chemistry and cheminformatic analysis and generated compounds appropriate for animal testing. We will test these compounds an in vivo model of DKD. This program will ultimately advance our molecular understanding of podocyte pathology in DKD, identify novel therapeutic targets, and generate probe/lead compounds for investigating and validating those targets in vivo.
Data for this report has not yet been released.