Acute renal failure (ARF) is an important cause of morbidity and mortality in hospitalized patients. Most ARF can be traced to ischemic injury due to a variety of etiologies. Unfortunately, no effective treatment strategies for ischemic renal injury exist, and thus the mortality rate of patients with severe ARF requiring dialysis has not decreased significantly over the last half century despite advances in supportive care. We have discovered a novel BMP signaling receptor, Dragon, whose expression in renal tubular cells is dynamically altered in ischemic renal injury. We propose to test the novel hypothesis that Dragon function will be important in the process of repair of the ischemic injured kidney. Knowledge we gain regarding the mechanism of action of Dragon and of the role of Dragon in the kidney would be of considerable importance in furthering our understanding of ischemic renal injury and ARF, and could be useful in eventual development of potential new diagnostic and treatment strategies. Bone Morphogenetic Proteins (BMPs) are members of the transforming growth factor beta (TGF-beta) superfamily of growth factors that regulate many physiologic and pathophysiologic processes in the kidney including nephrogenesis, response to injury, and repair. Although their precise role in the adult kidney is not fully understood, BMPs appear to be protective against renal injury to a variety of insults including ischemia. We present Preliminary Studies that Dragon, a novel GPI-anchored protein which we have recently discovered, is highly expressed in the kidney in renal tubular epithelial cells and that its expression is dynamically altered during ischemic renal injury. Importantly, we demonstrate that 1) Dragon can augment signaling via the BMP pathway, 2) Dragon can bind to specific BMPs, 3) Dragon signals via the BMP type IB receptor, ALK6, and 4) Dragon signals via the R-Smad, Smad1. We propose to investigate further the molecular and cellular mechanisms of Dragon-mediated signaling via the BMP pathway in kidney cells and to study in detail Dragon expression and its consequences in the kidney during ischemic injury and repair.
Showing the most recent 10 out of 30 publications
