Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis
| Autor: | Madison Purvis, Heng Jin, Chongyu Ren, Massimo Attanasio, Yanfen Chai, Chao Cao, Prerna Rastogi, Anton M. Jetten, Qiong Ding, Dongmei Lu, Shan Shanshan Wang, Sarah Elhadi, Yan Zhang, Dingxiao Liu, Angela Wang, Peter Igarashi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Senescence Kruppel-Like Transcription Factors Apoptosis Nerve Tissue Proteins Biology Article Pathology and Forensic Medicine Mice 03 medical and health sciences 0302 clinical medicine GLIS2 Nephronophthisis medicine Animals Senolytic Cellular Senescence Gene knockout Mice Knockout Innate immune system Kidney Diseases Cystic medicine.disease Immunity Innate Toll-Like Receptor 2 Mice Inbred C57BL Disease Models Animal TLR2 Kidney Tubules 030104 developmental biology 030220 oncology & carcinogenesis Myeloid Differentiation Factor 88 Knockout mouse Cancer research |
| Zdroj: | Am J Pathol |
| ISSN: | 0002-9440 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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