The role of beta agonists in the treatment of chronic kidney disease

Diseases affecting podocytes and the glomerulus, such as diabetes, are the leading cause of end stage kidney disease (ESKD). Eleven percent of Veterans meet the established criteria for chronic kidney disease (CKD), which leads to ESKD and premature death from cardiovascular disease. The vast majority of research in the field of CKD has focused on the initiating events and causes of CKD; unfortunately, this approach does not represent what is seen clinically where CKD is identified after the injury occurs. Because therapeutic options for recovery from CKD are either severely limited or non-existent, there is a critical need for novel targets and therapeutics. The goal here is to validate a novel therapeutic target, the beta 2 adrenergic receptor (β2-AR), that we recently showed accelerates recovery of glomerular function following injury. Glomerular function is highly dependent on specialized cells known as podocytes, which are critical components of glomeruli. While podocyte injury is a common denominator in many glomerular diseases, there are no specific drugs that restore injury-induced loss of podocyte structure and function. Bioinformatics analysis following injury revealed induction of genes related to mitochondrial function. Mutations in mitochondrial genes are known to result in mitochondrial dysfunction and have been implicated in the loss of podocyte function. Since mitochondria are known to play a critical role in maintaining podocyte energy homeostasis, we hypothesized that podocytes could recover from injury by increasing mitochondrial biogenesis, and therapeutics that increase mitochondrial biogenesis would promote recovery from glomerular injury. To test this hypothesis, we investigated whether stimulation of the β2-AR by an agonist would induce mitochondrial biogenesis and restore glomerular filtration function in injured mice. Our recently published studies and preliminary data show a potent induction of mitochondrial biogenesis in podocytes by the long-acting β2-AR agonist formoterol. Importantly, using mouse models of podocyte injury, we demonstrated that oral and intraperitoneal administration of formoterol six hours following injury, when glomerular dysfunction is already established, restored glomerular structures, significantly reduced proteinuria, and accelerated recovery of glomerular function. We also show preliminary data indicating that Veterans with CKD and chronic obstructive pulmonary disease (COPD), who use β2-AR agonists, have a significantly slower decline of renal function. Since diabetes is the leading cause of CKD and ESKD, these clinical findings are most likely due to the effect of β2-AR agonists on diabetic nephropathy. Indeed, we have new data showing that formoterol use results in recovery from diabetic nephropathy in a mouse model of type II diabetes. Thus, we further hypothesize that treatment with formoterol accelerates the recovery of glomerular function following injury through the induction of podocyte mitochondrial biogenesis. To test this, we will investigate β2-AR-dependent mechanisms that participate in podocyte recovery by utilizing β2-AR knockout mice (β2-ARfl/fl;podocin-CreTg/+) and β2-AR-deficient podocytes derived from these mice. This will allow us to determine the mechanism of action of formoterol and possibly identify even more efficacious treatments (Aim 1). We will then assess the clinical value of using formoterol to molecularly target β2-AR-induced mitochondrial biogenesis to prevent or slow podocytopathy and CKD in a wide range of glomerular diseases, including Alport syndrome, loss of the podocyte slit diaphragm protein CD2AP, lupus nephritis, and diabetic nephropathy, the single most common cause of CKD and ESKD (Aim 2). Finally, we will perform a large retrospective cohort study to further evaluate the association between long- term β2-AR agonist use and decreased loss of renal function that we have identified in Veterans (Aim 3). Successful completion of this proposal, using a multifaceted approach that includes cell culture, animal experiments and human studies, will provide justification for a prospective randomized clinical trial to establish β2-AR agonists, which are both safe and inexpensive, as an efficacious treatment for CKD.