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Published on: June 23, 2015
Cyst expansion and regression in a mouse model of polycystic kidney disease
Hester Happé1, Annemieke M van der Wal, Daniela C F Salvatori
1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Abstract:
Autosomal-dominant polycystic kidney disease is characterized by progressive cyst formation and fibrosis in the kidneys. Here we describe an orthologous Pkd1(nl,nl) mouse model, with reduced expression of the normal Pkd1 transcript, on a fixed genetic background of equal parts C57Bl/6 and 129Ola/Hsd mice (B6Ola-Pkd1(nl,nl)). In these mice, the first cysts develop from mature proximal tubules around birth. Subsequently, larger cysts become visible at day 7, followed by distal tubule and collecting duct cyst formation, and progressive cystic enlargement to develop into large cystic kidneys within 4 weeks. Interestingly, cyst expansion was followed by renal volume regression due to cyst collapse. This was accompanied by focal formation of fibrotic areas, an increased expression of genes involved in matrix remodeling and subsequently an increase in infiltrating immune cells. After an initial increase in blood urea within the first 4 weeks, renal function remained stable over time and the mice were able to survive up to a year. Also, in kidneys of ADPKD patients collapsed cysts were observed, in addition to massive fibrosis and immune infiltrates. Thus, B6Ola-Pkd1(nl,nl) mice show regression of cysts and renal volume that is not accompanied by a reduction in blood urea levels.
Insights
A novel mouse model of autosomal-dominant polycystic kidney disease (ADPKD) exhibits cyst regression and renal volume reduction. This ADPKD model shows fibrosis and immune cell infiltration, mirroring human disease progression.
Area of Science:
- Nephrology
- Genetics
- Pathology
Background:
- Autosomal-dominant polycystic kidney disease (ADPKD) is a genetic disorder causing progressive kidney cyst formation and fibrosis.
- Understanding ADPKD pathogenesis is crucial for developing effective therapies.
Purpose of the Study:
- To characterize a novel Pkd1(nl,nl) mouse model (B6Ola-Pkd1(nl,nl)) that mimics key features of human ADPKD.
- To investigate cyst development, renal volume changes, fibrosis, and immune responses in this model.
Main Methods:
- Generation of the B6Ola-Pkd1(nl,nl) mouse model with reduced Pkd1 transcript expression.
- Longitudinal observation of cyst formation, renal volume, fibrosis, gene expression, and immune cell infiltration.
- Comparison of pathological findings with human ADPKD kidneys.
Main Results:
- Cyst formation initiated in proximal tubules around birth, progressing to involve distal tubules and collecting ducts within 4 weeks.
- Observed renal volume regression due to cyst collapse, accompanied by fibrosis and increased matrix remodeling gene expression.
- Increased immune cell infiltration was noted, and while blood urea initially rose, renal function remained stable, with mice surviving up to one year.
Conclusions:
- The B6Ola-Pkd1(nl,nl) mouse model recapitulates key ADPKD features, including cyst collapse and renal volume regression.
- This model exhibits significant fibrosis and immune infiltrates, similar to human ADPKD kidneys.
- The observed cyst regression without improved blood urea levels offers insights into ADPKD pathophysiology.
