Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease

Chao Zhang, Michael Rehman, Xin Tian, Steven Lim Cho Pei, Jianlei Gu, Thomas A. Bell, Ke Dong, Ming Shen Tham, Yiqiang Cai, Zemeng Wei, Felix Behrens, Anton M. Jetten, Hongyu Zhao, Monkol Lek and Stefan Somlo ()
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Chao Zhang: Department of Internal Medicine, Yale School of Medicine
Michael Rehman: Department of Internal Medicine, Yale School of Medicine
Xin Tian: Department of Internal Medicine, Yale School of Medicine
Steven Lim Cho Pei: Department of Internal Medicine, Yale School of Medicine
Jianlei Gu: Yale University School of Public Health
Thomas A. Bell: Ionis Pharmaceuticals, Inc.
Ke Dong: Department of Internal Medicine, Yale School of Medicine
Ming Shen Tham: Department of Internal Medicine, Yale School of Medicine
Yiqiang Cai: Department of Internal Medicine, Yale School of Medicine
Zemeng Wei: Department of Internal Medicine, Yale School of Medicine
Felix Behrens: Department of Internal Medicine, Yale School of Medicine
Anton M. Jetten: National Institutes of Health
Hongyu Zhao: Yale University School of Public Health
Monkol Lek: Yale School of Medicine
Stefan Somlo: Department of Internal Medicine, Yale School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Mouse models of autosomal dominant polycystic kidney disease (ADPKD) show that intact primary cilia are required for cyst growth following the inactivation of polycystin-1. The signaling pathways underlying this process, termed cilia-dependent cyst activation (CDCA), remain unknown. Using translating ribosome affinity purification RNASeq on mouse kidneys with polycystin-1 and cilia inactivation before cyst formation, we identify the differential ‘CDCA pattern’ translatome specifically dysregulated in kidney tubule cells destined to form cysts. From this, Glis2 emerges as a candidate functional effector of polycystin signaling and CDCA. In vitro changes in Glis2 expression mirror the polycystin- and cilia-dependent changes observed in kidney tissue, validating Glis2 as a cell culture-based indicator of polycystin function related to cyst formation. Inactivation of Glis2 suppresses polycystic kidney disease in mouse models of ADPKD, and pharmacological targeting of Glis2 with antisense oligonucleotides slows disease progression. Glis2 transcript and protein is a functional target of CDCA and a potential therapeutic target for treating ADPKD.

Date: 2024
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DOI: 10.1038/s41467-024-48025-6

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