The goal of this project is to validate a lead drug that will accelerate the recovery of glomerular function after injury. Glomerular function is highly dependent on specialized cells known as podocytes, which are the critical components of glomerular filtration system and whose loss results in progressive renal failure. While podocyte injury is a common denominator in many glomerular diseases including focal and segmental glomerulosclerosis (FSGS), specific drugs that can restore injury-induced loss of podocyte structure and function remain unknown. As part of our therapeutic target identification program in podocytes, we performed mRNA profiling of cultured podocytes that were injured with adriamycin. The bioinformatics analysis revealed induction of genes related to mitochondrial function. Mutations in mitochondrial genes are known to result in mitochondrial dysfunction and FSGS, and have been implicated in the loss of podocyte function. Podocytes are terminally differentiated cells that have lost mitotic activity, and typically do not proliferate after injury. It is known that mitochondria play a critical role in maintaining podocyte energy homeostasis. We propose that podocytes can recover from injury by increasing MB (mitochondrial biogenesis) and therapeutics that increases MB will promote recovery from glomerular injury. To investigate this hypothesis, we tested the effect of a lead drug that is known to be a potent and efficacious inducer of MB, on the recovery of glomerular injury in mice. Our preliminary studies show that this drug is a potent inducer of MB in podocytes. Importantly, using a mouse model of podocyte injury that mimics FSGS phenotype, we demonstrate that the oral or intraperitoneal administration of this drug in mice, 6h after the injury, when glomerular dysfunction is established, accelerated the recovery of glomerular function, significantly reduced proteinuria and restored glomerular structure. Thus we hypothesize that this therapeutic treatment accelerates the recovery of glomerular function following injury through induction of podocyte MB. To address this hypothesis, we propose the following specific aims:
Specific Aim 1 : Determine the efficacy and potency of this drug in inducing MB and function in mice glomeruli following injury.
Specific Aim 2 : Determine the efficacy and potency of this drug in accelerating recovery from injury in various mouse models of glomerulopathy that mimic human FSGS. This will also test the spectrum of glomerular diseases that can be targeted with this drug.
Specific Aim 3 : Since this drug associates with albumin, which is heavily excreted in nephrotic syndrome patients, we will measure the pharmacokinetic data for this agent in nephrotic mice during the course of induced disease to determine the effect of albuminuria on its half-life and metabolism. Successful completion of these experiments will establish this lead drug as an efficacious treatment for glomerular diseases particularly FSGS that specifically targets podocyte dysfunction.
The incidences of glomerular diseases such as FSGS are growing at a rapid pace, and is one of the leading causes of nephrotic syndrome resulting in ESRD (End Stage Renal Failure) worldwide. Limitations in treatment options warrant more research into the novel therapeutic interventions that are needed to fight the challenges in treating FSGS patients. This proposal will test the potency and efficacy of a lead therapeutic compound formoterol in treating FSGS like symptoms in mice models of glomerulopathy, thereby establishing formoterol as a frontline therapy to treat conditions like FSGS.
