Kidney disease affects more than 20 million people in the United States and is the 8th leading cause of death. It is also one of the costliest complications of chronic illness, such as hypertension and diabetes. Advances in kidney regeneration that could slow or reverse progression to kidney failure will have a major impact on human health. A long-term goal of cell-based therapies for kidney regeneration is to use engineered renal progenitor cells to generate new nephrons and replace damaged nephrons in injured kidneys. Renal progenitor cells are also being explored for use in generating nephrons ex vivo in engineered or natural organ scaffolds. In either case, nephron function requires a patent lumen for filtrate flow, processing, and homeostasis; i.e., proper plumbing. Tubule lumen interconnections are established normally during renal development by invasion of the ureter epithelium by cells of the distal S-shaped body. However, in a mature kidney, implanted renal progenitor cells may differentiate into tubules but fail to connect to an existing branched collecting system and do not contribute to kidney function. This proposal aims to overcome this hurdle by identifying growth factors that mediate nephron tubule-collecting duct fusion and determine how tubule interconnection can be induced during renal regeneration. Using the zebrafish adult kidney as a model of synchronous nephron tubule-collecting duct fusion we will 1) screen well-established Wnt and FGF signaling pathways with small molecule inhibitors and assay tubule interconnection and 2) test the effect of spatially and temporally restricted expression of growth factors or dominant negative small GTPase signaling inhibitors on nephron tubule- collecting duct fusion. These studies will provide important new insights about an essential but understudied cellular mechanism that is required for cell and tissue-based renal regeneration therapies.

Public Health Relevance

The kidney filters and processes the blood to maintain the proper fluid environment for all body cells. For kidney filtering units, nephrons, to function and conduct fluid, they must make new connections to existing tubules and generate functional kidney 'plumbing'. We aim to show how this happens and how the process of making new tubule connections can be stimulated to increase the capacity of an injured kidney to process fluid and avert kidney failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
Project #
5UH3DK107372-04
Application #
9564667
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Hoshizaki, Deborah K
Project Start
2015-09-23
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Oxburgh, Leif; Carroll, Thomas J; Cleaver, Ondine et al. (2017) (Re)Building a Kidney. J Am Soc Nephrol 28:1370-1378
Tang, Qin; Iyer, Sowmya; Lobbardi, Riadh et al. (2017) Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing. J Exp Med 214:2875-2887