Tubulointerstitial fibrosis, a common endpoint outcome of a wide range of chronic kidney diseases (CKD), is preceded by activation of the a-smooth muscle actin-positive myofibroblasts, the principal effector cells that are responsible for the over-production of extracellular matrix components. This is the A1 revision of a R01 competitive renewal application, which proposes to continue our long- term efforts to elucidate the origins, activation and regulation of myofibroblasts in renal fibrogenesis. Studies in previous project period of this application indicate that dysregulated activation of key developmental signaling such as sonic hedgehog (Shh) and Wnt/beta-catenin plays a critical role in mediating fibroblast activation and renal fibrosis. In this renewal application, studies are designed to testa central hypothesis that Shh and Wnts mediate a two-way cross-talk between tubular epithelium and interstitial fibroblasts, and such 'epithelial-mesenchymal communication (EMC)'plays an essential role in promoting fibroblast activation and matrix production. The entire application consists of three specific aims.
Aim 1 is to investigate the role of tubule-derived Shh in promoting fibroblast proliferation and activation.
Aim 2 is to investigate the role of fibroblast-derived Wnts in mediating the fibrogenic responses of tubular epithelium.
Aim 3 is to investigate the therapeutic effects of blocking Shh or/and Wnt signaling with small molecule inhibitors or endogenous antagonist on renal fibrosis. These studies promise to offer important insights into understanding how tubular injury in diseased kidneys drives fibroblast proliferation and activation, leading to excessive matrix production and scar formation. Undoubtedly, the data generated from this application will have wide implications in comprehending the pathogenesis of renal fibrosis after injury, as well as in designing future therapeutic regimens for treatment.

Public Health Relevance

It is estimated that up to 13% of the US adult population has some degree of chronic kidney disease (CKD), characterized by kidney function decline and tissue fibrosis. CKD often progresses into end- stage renal failure, a devastating condition requiring renal replacement therapy. The studies proposed in this application promises to provide important insights into understanding the patho-mechanism of renal fibrosis, and may offer unique opportunities for designing rational strategies for the treatment of human fibrotic CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064005-10
Application #
8695332
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2003-05-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
$334,950
Indirect Cost
$117,450
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zhou, Dong; Li, Yingjian; Zhou, Lili et al. (2014) Sonic hedgehog is a novel tubule-derived growth factor for interstitial fibroblasts after kidney injury. J Am Soc Nephrol 25:2187-200
Tan, Roderick J; Liu, Youhua (2014) Arrestin(g) podocyte injury with endothelin antagonism. J Am Soc Nephrol 25:423-5
Tan, Roderick J; Liu, Youhua (2013) Macrophage-derived TGF-* in renal fibrosis: not a macro-impact after all. Am J Physiol Renal Physiol 305:F821-2
Zhou, Dong; Tan, Roderick J; Zhou, Lili et al. (2013) Kidney tubular *-catenin signaling controls interstitial fibroblast fate via epithelial-mesenchymal communication. Sci Rep 3:1878
Zhou, Lili; Li, Yingjian; Zhou, Dong et al. (2013) Loss of Klotho contributes to kidney injury by derepression of Wnt/?-catenin signaling. J Am Soc Nephrol 24:771-85
Zhou, Dong; Tan, Roderick J; Lin, Lin et al. (2013) Activation of hepatocyte growth factor receptor, c-met, in renal tubules is required for renoprotection after acute kidney injury. Kidney Int 84:509-20
He, Weichun; Tan, Roderick J; Li, Yingjian et al. (2012) Matrix metalloproteinase-7 as a surrogate marker predicts renal Wnt/ýý-catenin activity in CKD. J Am Soc Nephrol 23:294-304
Ding, Hong; Zhou, Dong; Hao, Sha et al. (2012) Sonic hedgehog signaling mediates epithelial-mesenchymal communication and promotes renal fibrosis. J Am Soc Nephrol 23:801-13
Tan, Roderick J; Liu, Youhua (2012) Matrix metalloproteinases in kidney homeostasis and diseases. Am J Physiol Renal Physiol 302:F1351-61
Li, Yingjian; Wen, Xiaoyan; Liu, Youhua (2012) Tubular cell dedifferentiation and peritubular inflammation are coupled by the transcription regulator Id1 in renal fibrogenesis. Kidney Int 81:880-91

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