Chronic kidney disease (CKD) affects ~15% of the U.S. population. Although a broad range of insults initiate kidney injury, fibrosis is a hallmark of all forms of progressive CKD. In spite of advances in delineating pathways that contribute to kidney fibrosis, there are no specific treatments for this serious disorder. TGF-? signaling is a central mediator of fibrosis in multiple tissues making it an attractive therapeutic target. However, because these cytokines have a wide range of roles in human physiology and pathology, the challenge has been to find a therapeutic strategy that is selective for the diseased target tissue to improve efficacy and safety profiles. A promising approach is to disrupt TGF-? activation in the injured tissue. TGF-? is secreted as a latent, inactive complex that is sequestered in high concentrations in the extracellular matrix. A critical step in the regulation of TGF-? signaling is activation of the latent complex by binding of alpha v (?v) integrins to lysine-glycine-aspartic acid (RGD) motifs.
In Aim 1 of this proposal, we will determine if a novel small molecule RGD peptidomimetic inhibitor of TGF-? activation will reduce kidney fibrosis in mouse models of nephrotoxicity, ischemia and urinary tract obstruction. Our preliminary studies indicated that this compound is safe and effective and thus a highly promising candidate for future translational studies in patients. Developing effective treatments for kidney disease requires increased knowledge about molecular mechanisms that drive progressive fibrosis of the organ. Myofibroblasts, derived from peri-vascular mesenchymal progenitor cells are the principal source of extracellular matrix deposition in organ fibrosis. However, the cellular and molecular pathways that control the formation of these cells in response to injury are not well understood.
In Aim 2, we will investigate the molecular mechanisms by which alpha v (?v) integrins regulate the proliferation and differentiation of myofibroblasts after injury. These pre-clinical studies will advance knowledge about mechanisms of organ fibrosis and have the potential to identify a novel therapeutic strategy to treat chronic kidney disease in veterans.
Every year ~3000-3500 veterans are diagnosed with chronic kidney disease. In many of these affected individuals there is progressive kidney fibrosis leading to end stage organ failure and a need for dialysis and transplantation. Currently, more than 10,000 veterans are receiving dialysis in the VA health care system. In addition, chronic kidney disease is a major risk factor for cardiovascular morbidity and mortality. The risk of kidney failure increases with age and disproportionately affects African Americans, populations that are highly represented among veterans. Current treatments are of limited efficacy and thus there is a pressing need to develop new approaches that can reduce the burden of this disease.