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.
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Acknowledgements
We thank the George M. O’Brien Kidney Center at Yale (P30 DK079310) for assistance with BAC recombineering and BUN measurements. This work was supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases grants (nos. R01 DK121948 and RC1 DK086738 to S.S.) and a PKD Foundation grant (no. 196F14 to M.M.). We thank the Amy P. Goldman Foundation for their generous and steadfast support.
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K.D., C.Z., X.T. and M.M. performed the experiments. D.C. and F.H. performed and analyzed the MRI studies. S.S. conceived the study. K.D. and S.S. designed the study and analyzed the data. K.D. and S.S. prepared the figures. S.S. wrote the manuscript with input from all the authors.
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Dong, K., Zhang, C., Tian, X. et al. Renal plasticity revealed through reversal of polycystic kidney disease in mice. Nat Genet 53, 1649–1663 (2021). https://doi.org/10.1038/s41588-021-00946-4
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DOI: https://doi.org/10.1038/s41588-021-00946-4
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