The kidney has an inherent ability to regenerate following damage. This repair is concomitant with the expression of transcription factor genes such as Pax2 and Lhx1, which are essential for initiating normal kidney organogenesis, suggesting that regenerating tubular cells arise from cells with a primitive, progenitor-like state. Renal progenitors may be formed following the 're-programming'of tubular epithelial cells, such as in mammals, or from cells that permanently reside in the kidney, such as in the adult zebrafish. We hypothesize that any treatment that expands or enhances renal progenitors will accelerate the rate of recovery following acute kidney injury (AKI). To test this we developed larval and adult models of AKI in zebrafish and developed unique tools and methodologies to manipulate renal progenitors. We performed a high-content screen to identify compounds that enhance renal progenitor cell number and identified a novel class of histone deacetylase inhibitors (HDACis) that accelerates renal recovery in zebrafish and mouse models of AKI when given after the induction of injury. The proposed work is divided into three specific aims, which take advantage of the complementary expertise of investigators at two different institutions.
Aim 1 : We will test whether HDAC inhibition accelerates the rate of recovery following AKI by inducing the proliferation of renal progenitor cells and/or the expression of genes involved in kidney organogenesis.
Aim 2 : We will determine the importance of Pax2/Pax8 and Lhx1 during normal kidney organogenesis and during the regenerative response by performing loss-of-function and gain-of-function experiments.
Aim 3 : We wil identify cofactors that comprise the Lhx1 transcriptional complex in order to better understand how this critical factor is involved in activating a kidney program in renal progenitors.

Public Health Relevance

Acute kidney injury (AKI) is a common and largely reversible disorder that has a high mortality but for which there is no specific treatment in humans. Our studies have identified (A) a new class of histone deacetylase inhibitors that accelerate the rate of renal recovery following AKI and (B) a renal progenitor cell population in the adult zebrafish that regenerates damaged kidney tissue. The purpose of our proposed studies is to determine the molecular mechanism by which these agents act to enhance renal regeneration with the ultimate goal of developing new therapies to treat AKI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069403-08
Application #
8626385
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2004-12-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
8
Fiscal Year
2014
Total Cost
$305,066
Indirect Cost
$83,070
Name
University of Pittsburgh
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sander, Veronika; Davidson, Alan J (2014) Kidney injury and regeneration in zebrafish. Semin Nephrol 34:437-44
Cirio, M Cecilia; de Groh, Eric D; de Caestecker, Mark P et al. (2014) Kidney regeneration: common themes from the embryo to the adult. Pediatr Nephrol 29:553-64
Naylor, Richard W; Davidson, Alan J (2014) Hnf1beta and nephron segmentation. Pediatr Nephrol 29:659-64
Novitskaya, Tatiana; McDermott, Lee; Zhang, Ke Xin et al. (2014) A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury. Am J Physiol Renal Physiol 306:F496-504
Sanker, Subramaniam; Cirio, Maria Cecilia; Vollmer, Laura L et al. (2013) Development of high-content assays for kidney progenitor cell expansion in transgenic zebrafish. J Biomol Screen 18:1193-202
Cianciolo Cosentino, Chiara; Skrypnyk, Nataliya I; Brilli, Lauren L et al. (2013) Histone deacetylase inhibitor enhances recovery after AKI. J Am Soc Nephrol 24:943-53
Naylor, Richard W; Przepiorski, Aneta; Ren, Qun et al. (2013) HNF1* is essential for nephron segmentation during nephrogenesis. J Am Soc Nephrol 24:77-87
Swanhart, Lisa M; Cosentino, Chiara Cianciolo; Diep, Cuong Q et al. (2011) Zebrafish kidney development: basic science to translational research. Birth Defects Res C Embryo Today 93:141-56
Hukriede, Neil A; Dawid, Igor B (2011) Making a tubule the noncanonical way. J Am Soc Nephrol 22:1575-7
Cirio, M Cecilia; Hui, Zhao; Haldin, Caroline E et al. (2011) Lhx1 is required for specification of the renal progenitor cell field. PLoS One 6:e18858

Showing the most recent 10 out of 15 publications