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

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.

Inflammation and Premature Ageing in Chronic Kidney Disease

“…In accordance with this hypothesis, the cyclin-dependent kinase inhibitor roscovitine reduces cyst formation in mice with PKD [127]. In contrast, nephronophthisis, another cystic kidney disease, is characterized by cellular senescence [133]. Furthermore, senolytic treatment in mice with nephronophthisis type 7 improves cystic area, inflammation, and renal fibrosis [134].…”

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

“…However, no direct role for MERTK in regulation of ciliation has previously been defined. Activation of CHEK1/CHK1 has been reported to be a consequence of loss of the Glis2/Nphp7 gene, which is associated with progressive kidney atrophy and reverses cystogenesis arising from Kif mutation (59). CHK1 was also described as interacting physically and functionally with NEK8 to regulate DNA damage response in the renal ciliopathy associated with loss of NEK8 (60).…”

Epithelial innate immunity mediates tubular cell senescence after kidney injury

“…SA-β-Gal staining. Kidneys were fixed in 4% PFA and incubated in 18% sucrose as previously described (59). Frozen sections (8 μm) were air dried for 20 minutes and then incubated at 37°C for 12 to 16 hours in fresh SA-β-Gal staining solution with 1 mg/ml X-Gal (Teknova) in dimethylformamide, 40 mM citric acid/ sodium phosphate (pH 6.0), 5 mM potassium ferrocyanide, 150 mM NaCl, and 2 mM MgCl 2 .…”