Chronic kidney diseases are major health problems that affect over 30 million Americans and the incidence is increasing at an alarming 16% in the last decade. The kidney is an intricate organ that requires coordinated regulation by distinct cell types and complex networks of genes to ensure its proper development and function. Kidney diseases are thus multifactorial and complex. The underlying causes to progression to kidney failure and the treatment and prevention of kidney diseases remain a challenge. We discovered that COUP-TFII, a transcription factor that regulates cell fate determination, embryonic development and adult organ function, plays a role in kidney development, function and disease. Several major cell types in the kidney express COUP-TFII. At the onset of kidney development (E10.5), COUP-TFII is expressed in the metanephric blastema, the urogenital ridge, and the metanephric mesenchyme (MM). Upon ureteric bud outgrowth, COUP-TFII is expressed in the condensed mesenchyme surrounding the ureteric buds and in the renal vesicle. At the nephrongenesis stage (E13.5), COUP-TFII becomes regionalized with high expression in the distal tubules and the glomeruli (podocytes and Bowman's capsule), but not detected in the proximal tubules. When COUP-TFII is conditionally ablated early, the MM cannot form properly and no kidney is formed. When COUP-TFII is knocked out at a later stage, very few nephrons are apparent and there is no detectable distal tubule, suggesting that COUP-TFII is critical for the formation and patterning of the nephron. Furthermore, adult mice with the loss of one COUP-TFII allele display polycystic kidneys, glomerulosclerosis (FSGS) and loss of kidney function, phenotypes resembling human kidney diseases. Preliminary results suggest that COUP-TFII regulates the expression of Angiopoietin 1, WT1, PKD1, TGF and many inflammatory genes, raising the possibility that COUP-TFII functions to protect the kidney from fibrosis, inflammation and from diabetic complications. To further define the defects of COUP-TFII mutants and dissect the underlying mechanism of COUP-TFII action, our specific aims in the next five years are: 1) Delineate the role of COUP-TFII in kidney development and its underlying mechanism;2) Determine the role of COUP-TFII in kidney function and diseases;and 3) Determine the role of COUP-TFII in diabetic nephropathy. Understanding the precise role of COUP-TFII in these diseases will provide timely insights that could be used in therapeutic strategies for the treatment and intervention of kidney diseases.

Public Health Relevance

Kidney diseases are major health hazards that affect over 30 million Americans. The various COUP-TFII deficient mouse models generated here will reveal how COUP-TFII affects kidney development and disease progression. Understanding COUP-TFII's mechanism of action will provide new avenues for the treatment of kidney diseases and diabetic complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045641-20
Application #
8288851
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
1992-09-30
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
20
Fiscal Year
2012
Total Cost
$422,719
Indirect Cost
$147,332
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Tang, Ke; Tsai, Sophia Y; Tsai, Ming-Jer (2015) COUP-TFs and eye development. Biochim Biophys Acta 1849:201-9
Lin, Shih-Chieh; Li, Yo-Hua; Wu, Meng-Hsing et al. (2014) Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. J Clin Endocrinol Metab 99:E427-37
Qin, Jun; Lee, Hui-Ju; Wu, San-Pin et al. (2014) Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. J Clin Invest 124:5013-26
Bosch, Daniƫlle G M; Boonstra, F Nienke; Gonzaga-Jauregui, Claudia et al. (2014) NR2F1 mutations cause optic atrophy with intellectual disability. Am J Hum Genet 94:303-9
Qin, Jun; Wu, San-Pin; Creighton, Chad J et al. (2013) COUP-TFII inhibits TGF-*-induced growth barrier to promote prostate tumorigenesis. Nature 493:236-40
Xie, Xin; Tang, Ke; Yu, Cheng-Tai et al. (2013) Regulatory potential of COUP-TFs in development: stem/progenitor cells. Semin Cell Dev Biol 24:687-93
Wu, San-pin; Cheng, Chiang-Min; Lanz, Rainer B et al. (2013) Atrial identity is determined by a COUP-TFII regulatory network. Dev Cell 25:417-26
Lin, Fu-Jung; Qin, Jun; Tang, Ke et al. (2011) Coup d'Etat: an orphan takes control. Endocr Rev 32:404-21
Xie, Xin; Qin, Jun; Lin, Sue-Hwa et al. (2011) Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation. Proc Natl Acad Sci U S A 108:14843-8
Qin, Jun; Chen, Xinpu; Xie, Xin et al. (2010) COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc Natl Acad Sci U S A 107:3687-92

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