Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis

Heng Jin; Yan Zhang; Dingxiao Liu; Shan Shanshan Wang; Qiong Ding; Prerna Rastogi; Madison Purvis; Angela Wang; Sarah Elhadi; Chongyu Ren; Chao Cao; Yanfen Chai; Peter Igarashi; Anton M Jetten; Dongmei Lu; Massimo Attanasio

doi:10.1016/j.ajpath.2019.09.013

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Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis

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Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis

Heng Jin, Yan Zhang, Dingxiao Liu, Shan Shanshan Wang, Qiong Ding, Prerna Rastogi, Madison Purvis, Angela Wang, Sarah Elhadi, Chongyu Ren, …

The American journal of pathology, Vol.190(1), pp.176-189

01/2020

DOI: 10.1016/j.ajpath.2019.09.013

PMCID: PMC6943802

PMID: 31676329

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Abstract

Nephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in >25 genes have been identified as causes of this disease that, in several cases, result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor-encoding GLIS2 cause NPHP type 7. Loss of function of mouse Glis2 causes senescence of kidney tubular cells. Senescent cells secrete proinflammatory molecules that induce progressive organ damage through several pathways, among which NF-κB signaling is prevalent. Herein, we show that the NF-κB signaling is active in Glis2 knockout kidney epithelial cells and that genetic inactivation of the toll-like receptor (TLR)/IL-1 receptor or pharmacologic elimination of senescent cells (senolytic therapy) reduces tubule damage, fibrosis, and apoptosis in the Glis2 mouse model of NPHP. Notably, in Glis2, Tlr2 double knockouts, senescence was also reduced and proliferation was increased, suggesting that loss of TLR2 activity improves the regenerative potential of tubular cells in Glis2 knockout kidneys. Our results further suggest that a combination of TLR/IL-1 receptor inhibition and senolytic therapy may delay the progression of kidney disease in NPHP type 7 and other forms of this disease.

Kidney Tubules - immunology

Nerve Tissue Proteins - physiology

Mice, Inbred C57BL

Kruppel-Like Transcription Factors - physiology

Kidney Diseases, Cystic - immunology

Kidney Diseases, Cystic - pathology

Mice, Knockout

Immunity, Innate - immunology

Cellular Senescence - immunology

Kidney Diseases, Cystic - metabolism

Animals

Toll-Like Receptor 2 - physiology

Myeloid Differentiation Factor 88 - physiology

Mice

Kidney Tubules - pathology

Kidney Tubules - metabolism

Apoptosis

Disease Models, Animal

Details

Title: Subtitle: Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis
Creators: Heng Jin - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
Yan Zhang - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
Dingxiao Liu - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Vascular Surgery, Second Xiangya Hospital, Central South University, Changsha, China
Shan Shanshan Wang - Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
Qiong Ding - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
Prerna Rastogi - Department of Pathology, University of Iowa, Iowa City, Iowa
Madison Purvis - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
Angela Wang - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
Sarah Elhadi - Division of Neprhology, Children's Hospital of Illinois, Peoria, Illinois
Chongyu Ren - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
Chao Cao - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
Yanfen Chai - Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
Peter Igarashi - Department of Internal Medicine, University of Minnesota, Minneapolis, Minnesota
Anton M Jetten - Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
Dongmei Lu - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
Massimo Attanasio - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa. Electronic address: massimo-attanasio@uiowa.edu
Resource Type: Journal article
Publication Details: The American journal of pathology, Vol.190(1), pp.176-189
DOI: 10.1016/j.ajpath.2019.09.013
PMID: 31676329
PMCID: PMC6943802
NLM abbreviation: Am J Pathol
ISSN: 0002-9440
eISSN: 1525-2191
Publisher: United States
Grant note: Z01 ES101565 / Intramural NIH HHS
Language: English
Date published: 01/2020
Academic Unit: Epidemiology; Pathology; Dental Research; Internal Medicine
Record Identifier: 9984066341702771

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