Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease

Dongmei Lu, Alysha Rauhauser, Binghua Li, Chongyu Ren, Kayla McEnery, Jili Zhu, Moumita Chaki, Komal Vadnagara, Sarah Elhadi, Anton M. Jetten, Peter Igarashi, Massimo Attanasio

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2 null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest.

Original languageEnglish (US)
Pages (from-to)1307-1323
Number of pages17
JournalKidney International
Volume89
Issue number6
DOIs
StatePublished - 2016

    Fingerprint

Keywords

  • cystic kidney disease
  • DNA damage
  • Kif3a
  • nephronophthisis
  • senescence

ASJC Scopus subject areas

  • Medicine(all)
  • Nephrology

Cite this

Lu, D., Rauhauser, A., Li, B., Ren, C., McEnery, K., Zhu, J., Chaki, M., Vadnagara, K., Elhadi, S., Jetten, A. M., Igarashi, P., & Attanasio, M. (2016). Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease. Kidney International, 89(6), 1307-1323. https://doi.org/10.1016/j.kint.2016.03.006