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Functional correction of renal defects in a mouse model for ARPKD through expression of the cloned wild-type Tg737
B K Yoder1, W G Richards, C Sommardahl
1Biology Division, Oak Ridge National Laboratory, Tennessee, USA.
Abstract:
Autosomal recessive polycystic kidney disease (ARPKD) is characterized by the formation of large collecting tubule and ductular cysts that often result in renal insufficiency within the first decade of life. Understanding the process leading to cyst formation will require the identification and characterization of genes involved in the etiology of this disease. In this regard, we previously described the generation of a mouse model (TgN737Rpw) for ARPKD and the cloning of a candidate gene. Here we show direct involvement of the Tg737 gene in collecting duct cyst formation by expressing the wild-type Tg737 cDNA as a transgene in TgN737Rpw mutants. In contrast to TgN737Rpw mutants, the "rescued" animals survive longer, have normal renal function and normal localization of the EGFr to the basolateral surfaces of collecting duct epithelium.
Insights
Autosomal recessive polycystic kidney disease (ARPKD) involves cyst formation in kidney collecting ducts. Restoring the Tg737 gene function in a mouse model prevents cyst development and restores normal kidney function.
Area of Science:
- Genetics
- Nephrology
- Molecular Biology
Background:
- Autosomal recessive polycystic kidney disease (ARPKD) causes kidney cysts and early renal insufficiency.
- Identifying genes responsible for ARPKD is crucial for understanding cystogenesis.
- A mouse model (TgN737Rpw) and a candidate gene (Tg737) were previously identified.
Purpose of the Study:
- To confirm the direct role of the Tg737 gene in ARPKD.
- To investigate the therapeutic potential of Tg737 gene restoration.
Main Methods:
- Generation of a mouse model for ARPKD (TgN737Rpw).
- Cloning of the candidate Tg737 gene.
- Expression of wild-type Tg737 cDNA as a transgene in ARPKD mutant mice.
Main Results:
- Transgenic expression of wild-type Tg737 cDNA rescued the ARPKD phenotype in mice.
- Rescued animals exhibited prolonged survival and normal renal function.
- Normal localization of the epidermal growth factor receptor (EGFr) to basolateral surfaces was restored.
Conclusions:
- The Tg737 gene is directly involved in collecting duct cyst formation in ARPKD.
- Tg737 gene restoration can ameliorate ARPKD pathology and restore kidney function.
- This study highlights Tg737 as a key player in ARPKD pathogenesis.