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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Wetendorf, Margeaux; Wu, San-Pin; Wang, Xiaoqiu et al. (2017) Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment. Biol Reprod 96:313-326
Zhao, Fei; Franco, Heather L; Rodriguez, Karina F et al. (2017) Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. Science 357:717-720
Xie, Xin; Wu, San-Pin; Tsai, Ming-Jer et al. (2017) The Role of COUP-TFII in Striated Muscle Development and Disease. Curr Top Dev Biol 125:375-403
Lee, Hui-Ju; Kao, Chung-Yang; Lin, Shih-Chieh et al. (2017) Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development. Sci Rep 7:3136
Wang, Leiming; Xu, Mafei; Qin, Jun et al. (2016) MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer. Oncotarget 7:14673-83
Xie, Xin; Tsai, Sophia Y; Tsai, Ming-Jer (2016) COUP-TFII regulates satellite cell function and muscular dystrophy. J Clin Invest 126:3929-3941
Wu, San-Pin; Yu, Cheng-Tai; Tsai, Sophia Y et al. (2016) Choose your destiny: Make a cell fate decision with COUP-TFII. J Steroid Biochem Mol Biol 157:7-12
Lin, Shih-Chieh; Kao, Chung-Yang; Lee, Hui-Ju et al. (2016) Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer. Nat Commun 7:11418
Wu, San-Pin; Kao, Chung-Yang; Wang, Leiming et al. (2015) Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nat Commun 6:8245
Tang, Ke; Tsai, Sophia Y; Tsai, Ming-Jer (2015) COUP-TFs and eye development. Biochim Biophys Acta 1849:201-9

Showing the most recent 10 out of 57 publications