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

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)176-189
Number of pages14
JournalAmerican Journal of Pathology
Volume190
Issue number1
DOIs
StatePublished - Jan 2020

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Jin, H., Zhang, Y., Liu, D., Wang, S. S., Ding, Q., Rastogi, P., Purvis, M., Wang, A., Elhadi, S., Ren, C., Cao, C., Chai, Y., Igarashi, P., Jetten, A. M., Lu, D., & Attanasio, M. (2020). Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis. American Journal of Pathology, 190(1), 176-189. https://doi.org/10.1016/j.ajpath.2019.09.013