Novel Small Molecules for Treating Kidney Disease
DESCRIPTION: Chronic kidney disease (CKD) is a significant and rapidly growing global health crisis. CKD is associated with cardiovascular disease, hypertension, diabetes, obesity, and aging. It is characterized by gradual loss of renal function with increasing proteinuria (albuminuria), interstitial fibrosis, and glomerulosclerosis. Small increases in urinary protein are associated with markedly increased morbidity and mortality. Thus, proteinuria is an important therapeutic target in modern medicine. We have used an in vitro method to study glomerular function and have shown that the glomerular protein barrier is impaired prior to the onset of overt proteinuria in animal models of several human diseases. These models include hypertension, diabetes mellitus, and the primary glomerular disease, focal segmental glomerulosclerosis (FSGS). We have shown that a factor present in serum or plasma of patients with FSGS increases glomerular albumin permeability in vitro (Palb) and causes proteinuria in rats. In the proposed studies, we will use the glomerular injury caused by this factor as a model for testing potential therapeutic agents. We have shown that, i) 8,9-epoxyeicosatrienoic acid (8,9-EET) is required to maintain the integrity of the glomerular filtration barrier and, ii) 8,9-EET and synthetic analogs containing two double bonds (8,9-EEDs) protect the glomerular filtration barrier from the effects of FSGS permeability factor. The synthetic analogs of 8,9-EET are highly promising candidates for developing newtherapeutic molecules to preserve normal glomerular filtration barrier function and to manage/treat glomerular dysfunction associated with other causes of CKD. During Phase-1 of this project, we plan to address the following Specific Aims: 1. Prepare fivesynthetic 8,9-EED analogs containing epoxide bioisosteres. 2. Evaluate glomerular protection of these synthetic analogs using an in vitro glomerular albumin permeability assay. We will use established techniques and expert technical skills to obtain synthetic analogs of high purity and stability. Analogs will be tested and compared for their protective effect on the glomerular filtration barrier using the in vitro assay. These compounds will be used as lead compounds during the Phase-II of our SBIR project, and will ultimately lead to file an IND application evaluating in human subjects with proteinuria. PUBLIC HEALTH RELEVANCE: e Increased protein level in the urine is an early symptom of chronic kidney disease (CKD) in a large number of patients and is a consequence of damage to the filters (glomeruli) in the kidney that prevent blood proteins from passing into urine. CKD is a major health problem, especially among the elderly and those with diabetes or heart disease. Our work has identified a new class of compounds that, for the first time, will be useful in preventing and treating proteinuria and, therefore, avoiding or ameliorating the progression of chronic kidney disease.
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