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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069533-02
Application #
7023865
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Wilder, Elizabeth L
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$368,433
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Samir, Anthony E; Allegretti, Andrew S; Zhu, Qingli et al. (2015) Shear wave elastography in chronic kidney disease: a pilot experience in native kidneys. BMC Nephrol 16:119
Tesfay, Lia; Clausen, Kathryn A; Kim, Jin Woo et al. (2015) Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res 75:2254-63
Meynard, Delphine; Babitt, Jodie L; Lin, Herbert Y (2014) The liver: conductor of systemic iron balance. Blood 123:168-76
Liu, Wenjing; Li, Xiaoling; Zhao, Yueshui et al. (2013) Dragon (repulsive guidance molecule RGMb) inhibits E-cadherin expression and induces apoptosis in renal tubular epithelial cells. J Biol Chem 288:31528-39
Sun, Chia Chi; Vaja, Valentina; Chen, Shanzhuo et al. (2013) A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats. Nephrol Dial Transplant 28:1733-43
Meynard, Delphine; Sun, Chia Chi; Wu, Qifang et al. (2013) Inflammation regulates TMPRSS6 expression via STAT5. PLoS One 8:e82127
Robbins, Clinton S; Hilgendorf, Ingo; Weber, Georg F et al. (2013) Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 19:1166-72
Bouley, Richard; Nunes, Paula; Andriopoulos Jr, Billy et al. (2013) Heterologous downregulation of vasopressin type 2 receptor is induced by transferrin. Am J Physiol Renal Physiol 304:F553-64
Chen, Wenjie; Sun, Chia Chi; Chen, Shanzhuo et al. (2013) A novel validated enzyme-linked immunosorbent assay to quantify soluble hemojuvelin in mouse serum. Haematologica 98:296-304
Finer, Gal; Schnaper, H William; Kanwar, Yashpal S et al. (2012) Divergent roles of Smad3 and PI3-kinase in murine adriamycin nephropathy indicate distinct mechanisms of proteinuria and fibrogenesis. Kidney Int 82:525-36

Showing the most recent 10 out of 30 publications