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Published on: June 23, 2015
Renal plasticity revealed through reversal of polycystic kidney disease in mice
Ke Dong1, Chao Zhang1, Xin Tian1
1Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Abstract:
Initiation of cyst formation in autosomal dominant polycystic kidney disease (ADPKD) occurs when kidney tubule cells are rendered null for either PKD1 or PKD2 by somatic 'second hit' mutations. Subsequent cyst progression remodels the organ through changes in tubule cell shape, proliferation and secretion. The kidney develops inflammation and fibrosis. We constructed a mouse model in which adult inactivation of either Pkd gene can be followed by reactivation of the gene at a later time. Using this model, we show that re-expression of Pkd genes in cystic kidneys results in rapid reversal of ADPKD. Cyst cell proliferation is reduced, autophagy is activated and cystic tubules with expanded lumina lined by squamoid cells revert to normal lumina lined by cuboidal cells. Increases in inflammation, extracellular matrix deposition and myofibroblast activation are reversed, and the kidneys become smaller. We conclude that phenotypic features of ADPKD are reversible and that the kidney has an unexpected capacity for plasticity controlled at least in part by ADPKD gene function.
Insights
Reversing autosomal dominant polycystic kidney disease (ADPKD) is possible. Reactivating PKD genes in adult mice rapidly reversed ADPKD, reducing cyst size and restoring kidney function.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by cyst formation in the kidneys.
- Cyst initiation involves somatic 'second hit' mutations in PKD1 or PKD2 genes, leading to tubule cell dysfunction.
- Disease progression involves altered cell shape, proliferation, secretion, inflammation, fibrosis, and organ remodeling.
Purpose of the Study:
- To investigate the potential for reversing established ADPKD.
- To determine if re-expression of Pkd genes can ameliorate ADPKD phenotypes in a mouse model.
Main Methods:
- Development of a conditional mouse model allowing adult inactivation and subsequent reactivation of Pkd genes.
- Monitoring of kidney structure, cell proliferation, autophagy, inflammation, fibrosis, and organ size following gene re-expression.
Main Results:
- Re-expression of Pkd genes in adult cystic kidneys led to rapid reversal of ADPKD.
- Reduced cyst cell proliferation, activated autophagy, and reversion of abnormal tubule morphology.
- Reversal of increased inflammation, extracellular matrix deposition, and myofibroblast activation, resulting in smaller kidneys.
Conclusions:
- Phenotypic features of ADPKD are reversible.
- The kidney exhibits significant plasticity, influenced by ADPKD gene function.
- Targeted gene reactivation offers a potential therapeutic strategy for ADPKD.
