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Autosomal recessive polycystic kidney disease in a murine model. A gross and microscopic description
V H Gattone1, J P Calvet, B D Cowley
1Department of Anatomy, University of Kansas Medical Center, Kansas City.
Insights
Autosomal recessive polycystic kidney disease in C57BL/6J-cpk mice shows two phases: early proximal tubule changes and later collecting duct cysts. Cell proliferation is minimal, suggesting other mechanisms drive kidney enlargement.
Area of Science:
- Nephrology
- Genetics
- Developmental Biology
Background:
- Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder.
- The C57BL/6J-cpk mouse is a model for studying ARPKD pathogenesis.
- Understanding ARPKD mechanisms is crucial for potential therapeutic targets.
Purpose of the Study:
- To investigate the pathogenesis of renal cystic disease in the C57BL/6J-cpk murine model.
- To characterize the morphological and growth changes associated with ARPKD.
- To identify the cellular mechanisms underlying kidney enlargement in ARPKD.
Main Methods:
- Utilized C57BL/6J-cpk mice from fetal to 3-week-old stages.
- Employed light and electron microscopy for kidney morphology.
- Performed nephron segment microdissection.
- Assessed cell proliferation using mitotic index and Histone H4 gene expression.
Main Results:
- Identified two distinct phases of cystic disease development.
- Phase 1 (fetal/newborn): Proximal tubule enlargement, increased mitotic index, and cell necrosis.
- Phase 2 (1-3 weeks): Kidney enlargement due to collecting duct cysts, azotemia, and stunted growth. Minimal increase in cell proliferation markers observed.
Conclusions:
- ARPKD pathogenesis involves distinct early and late phases.
- Collecting duct cystic changes are primary drivers of kidney enlargement in later stages.
- The observed tubular enlargement occurs with minimal contribution from significant cell proliferation.
Abstract:
The C57BL/6J-cpk genetic murine model of autosomal recessive polycystic kidney disease was examined to gain insight into the pathogenesis of renal cystic disease. Fetal through 3-week-old offspring of heterozygote matings were used to study growth parameters and morphology of this genetic form of cystic disease. The kidneys were examined by light and electron microscopy and nephron segments were microdissected. Two phases of cystic disease development were morphologically identified. The first phase in fetal and newborn affected pups was characterized by proximal tubule enlargement and a general increase in the tubular mitotic index. The proximal tubules showed cytologic abnormalities along with an increased necrotic cell index. The later phase, in one through 3-week-old cystic pups, was characterized by progressive enlargement of the kidneys due mainly to cystic change of the collecting ducts and by development of azotemia. Secondary to the azotemia was a stunted body growth. Significant tubular epithelial hyperplasia was not found by mitotic index during the second phase, but an increase in collecting duct cellularity was present. Histone H4 gene expression, which is tightly coupled to DNA synthesis and thus an index of cell proliferation, showed only a minimal increase in cystic kidneys at 1, 2, and 3 weeks of age. Therefore, the degree of cell proliferation necessary to allow the observed tubular enlargement appears to be minimal.