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Published on: June 23, 2015
Progressive development of polycystic kidney disease in the mouse model expressing Pkd1 extracellular domain
Almira Kurbegovic1, Marie Trudel
1Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Universite de Montreal, Faculte de Medecine, Montreal, Quebec, Canada.
Insights
Researchers developed a novel mouse model for Autosomal dominant polycystic kidney disease (ADPKD) by creating transgenic mice with a specific Pkd1 gene mutation. These mice exhibit key ADPKD symptoms, offering new insights into the disease
Area of Science:
- Nephrology and Genetics
- Molecular and Cellular Biology
- Disease Modeling
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing kidney cysts and renal failure.
- Mutations in PKD1 (encoding polycystin-1/PC1) are the primary cause of ADPKD.
- Understanding the function of the PC1 extracellular domain is crucial for ADPKD research.
Purpose of the Study:
- To create a transgenic mouse model mimicking human PKD1 mutations.
- To investigate the role of the PC1 extracellular domain in ADPKD pathogenesis.
- To explore potential pathogenic crosstalk mechanisms in ADPKD.
Main Methods:
- Generation of four transgenic mouse lines expressing exclusively the extracellular domain of the Pkd1 gene (Pkd1(extra)).
- Analysis of transgene expression levels and protein abundance.
- Assessment of renal phenotype, function, and survival in transgenic mice.
Main Results:
- All four transgenic mouse lines developed a progressive renal cystic phenotype.
- Transgenic mice exhibited hallmark ADPKD features: proteinuria, renal insufficiency, anemia, and late-life renal failure.
- The Pkd1(extra) transgene modulated PC2 expression and implicated c-myc in cystogenesis.
Conclusions:
- The novel Pkd1(extra) mouse model accurately reproduces human ADPKD clinical progression and pathophysiology.
- This model provides a valuable tool for studying the PC1 extracellular domain's function in ADPKD.
- The findings reveal a potential Pc1-mutant/Pc2 pathogenic crosstalk and the role of c-myc in cystogenesis.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slow progression of multiple cysts in both kidneys that lead to renal insufficiency in mid-life or later. ADPKD is associated with mutations mainly in the PKD1 gene (encoding polycystin-1 or PC1) and less frequently in the PKD2 gene (encoding polycystin-2 or PC2). To mimic naturally occurring human PKD1 mutations and gain insight into the PC1 extracellular domain function, four transgenic mouse lines were established with exclusively the extracellular domain of the Pkd1 gene (Pkd1(extra)) under endogenous transcriptional regulation. Expression of the Pkd1(extra) transgene was 2- to 80-fold above endogenous levels. Strikingly, the Pc1(extra) protein was more abundant, proportionally to the endogenous levels. All four transgenic mouse lines consistently displayed progressive renal cystic phenotype. Consequently, these transgenic mice reproducibly developed renal functional alterations similar to human ADPKD with proteinuria, renal insufficiency, anemia and died of renal failure late in life. In precystic kidneys, the Pkd1(extra) transgene modulated Pc2 expression and thereby, uncovered a potential Pc1-mutant/Pc2 pathogenic crosstalk mechanism. Moreover, the pathophysiologic mechanism also implicates c-myc, a major modulator of cystogenesis. Altogether, the novel Pkd1(extra) mouse model is the first Pc1 extracellular mutant that reproduces human ADPKD clinical progression and physiopathology.
