Understanding normal mechanisms of kidney regeneration in response to injuries is of vital importance to developing new therapies to tackle the increasing burden of chronic kidney disease and organ failure. Although the adult mammalian kidney lacks nephron progenitors that could regenerate entire nephrons, nevertheless it has remarkable capacity to regenerate. Recent studies have focused predominantly on tubule regeneration, yet have failed to identify an epithelial progenitor cell in adult kidney. However, there has been little attention to the vasculature. The overall goal of this application is to identify and study adult kidney quiescent stem/progenitor cells. Accordingly, a team of four experts has come together bringing unique backgrounds and skills including stem cell biology. Renin cell biology, kidney development, glomerular and interstitial injuries, and Regenerative Medicine specifically identify and characterize latent progenitors lying within the kidney. In exciting new feasibility studies using unique genetic tools, these investigators have shown evidence of recent collaborations by identifying putative latent progenitor cells that are activated in response to kidney injuries and growth. These cells yield progeny that repopulate vascular mural cells of the glomerulus (podocytes) and interstitium (pericytes and endothelial cells). In the first year of this R24 application (Phase I, addressed here) the investigators plan to establish irrefutably the presence and capacity of these latent progenitors using two distinct but complementary state-of-the-art fate mapping techniques in kidneys. Assuming the success of Phase I, the Investigators will then propose Phase II (years 2-5 of the R24 application) in which they will methodically dissect how these progenitors are activated, what lineal restrictions exist in the progeny of these progenitors, study their capacity in aging, and attempt to harness these progenitors to promote kidney cell regeneration.

Public Health Relevance

Acute Kidney Injury, Chronic Kidney Disease and End Stage Kidney Disease are major health burdens. Understanding how the kidney regenerates in response to injuries is vital to generating new therapies that will prevent or limit the developmen of chronic kidney disease or end stage kidney disease. These initial studies will study progenitor cells in the adult kidney that have the capacity to generate new kidney cells, particularly of the blood vessels of the kidney. The investigators will determine how important these progenitors are in regeneration after kidney damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
1R24DK094768-01
Application #
8268567
Study Section
Special Emphasis Panel (ZDK1-GRB-N (J1))
Program Officer
Hoshizaki, Deborah K
Project Start
2012-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$533,425
Indirect Cost
$127,031
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Pippin, Jeffrey W; Glenn, Sean T; Krofft, Ronald D et al. (2014) Cells of renin lineage take on a podocyte phenotype in aging nephropathy. Am J Physiol Renal Physiol 306:F1198-209
Shankland, Stuart J; Pippin, Jeffrey W; Duffield, Jeremy S (2014) Progenitor cells and podocyte regeneration. Semin Nephrol 34:418-28
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Kawakami, Takahisa; Ren, Shuyu; Duffield, Jeremy S (2013) Wnt signalling in kidney diseases: dual roles in renal injury and repair. J Pathol 229:221-31
Friedman, Scott L; Sheppard, Dean; Duffield, Jeremy S et al. (2013) Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 5:167sr1
Lichtnekert, Julia; Kawakami, Takahisa; Parks, William C et al. (2013) Changes in macrophage phenotype as the immune response evolves. Curr Opin Pharmacol 13:555-64
Hutchison, Nicol; Fligny, Cecile; Duffield, Jeremy S (2013) Resident mesenchymal cells and fibrosis. Biochim Biophys Acta 1832:962-71
Ren, Shuyu; Duffield, Jeremy S (2013) Pericytes in kidney fibrosis. Curr Opin Nephrol Hypertens 22:471-80

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