. The primary goal of this proposal is to explore the hypothesis that the Notch pathway plays an important role in the development of chronic kidney disease and kidney fibrosis. We found via large scale genome screening that Notch pathway proteins are regulated in patients and animal models chronic kidney disease and fibrosis. In this application we propose to perform a systematic analysis to examine the role of renal tubular epithelial Notch signaling in the adult kidney at baseline and diseased kidneys. First we will examine whether tubular epithelial Notch signaling plays any role in the adult kidney homeostasis, aging and repair. Next we will analyze which Notch receptor and ligand isoforms is responsible for the renal damage during injury. The third specific aim will define the molecular mechanism of Notch induced epithelial dysfunction and interstitial fibrosis. The current proposal will built on our original observation and explore the role of Notch signaling in the adult kidney both at baseline and in injury models. These studies will help not only deepen our understanding of renal epithelial homeostasis, but also aid the potential development of Notch based inhibitors for chronic kidney disease.

Public Health Relevance

Approximately 20 million people in the US suffer from chronic kidney disease (CKD). CKD is associated with an approximately 5-fold increase in cardiovascular mortality. The prevalence of patients with end-stage renal disease (ESRD) reaches more than half a million people in the U.S. alone, and increases at a rate of 5-6% worldwide. The 5-year survival of patients who reaches ESRD is around 20%, which is worse than many different solid tumors. These data highlight the importance and urgency of the current problem in the medical community on a global scale. On phenotypic and histological levels, chronic kidney disease development follows a very similar path. Fibrosis of the kidney is the final common pathway leading to ESRD. Our studies aim to understand the molecular mechanism of kidney fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076077-07
Application #
8534096
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (04))
Program Officer
Rys-Sikora, Krystyna E
Project Start
2006-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$335,821
Indirect Cost
$125,933
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Reidy, Kimberly; Kang, Hyun Mi; Hostetter, Thomas et al. (2014) Molecular mechanisms of diabetic kidney disease. J Clin Invest 124:2333-40
Tao, Jianling; Polumbo, Christina; Reidy, Kimberly et al. (2014) A multicolor podocyte reporter highlights heterogeneous podocyte changes in focal segmental glomerulosclerosis. Kidney Int 85:972-80
Dember, Laura M; Susztak, Katalin (2014) Notch ties a knot on fistula maturation. J Am Soc Nephrol 25:648-50
Han, Seung Hyeok; Susztak, Katalin (2014) The hyperglycemic and hyperinsulinemic combo gives you diabetic kidney disease immediately. Focus on "Combined acute hyperglycemic and hyperinsulinemic clamp induced profibrotic and proinflammatory responses in the kidney". Am J Physiol Cell Physiol 306:C198-9
Wang, Yidong; Wu, Bingruo; Chamberlain, Alyssa A et al. (2013) Endocardial to myocardial notch-wnt-bmp axis regulates early heart valve development. PLoS One 8:e60244
Sweetwyne, Mariya T; Susztak, Katalin (2013) For better or worse: a niche for Notch in parietal epithelial cell activation. Kidney Int 83:988-90
Bonegio, Ramon; Susztak, Katalin (2012) Notch signaling in diabetic nephropathy. Exp Cell Res 318:986-92
Sirin, Yasemin; Susztak, Katalin (2012) Notch in the kidney: development and disease. J Pathol 226:394-403
Sharma, Shuchita; Sirin, Yasemin; Susztak, Katalin (2011) The story of Notch and chronic kidney disease. Curr Opin Nephrol Hypertens 20:56-61
Woroniecka, Karolina I; Park, Ae Seo Deok; Mohtat, Davoud et al. (2011) Transcriptome analysis of human diabetic kidney disease. Diabetes 60:2354-69

Showing the most recent 10 out of 20 publications