Epithelial innate immunity mediates tubular cell senescence after kidney injury
| Autor: | Dao-Fu Dai, Diana Zepeda-Orozco, Yan Zhang, Heng Jin, Angela Wang, Madison Purvis, Prerna Rastogi, Judith Campisi, Yanfen Chai, Dingxiao Liu, Chao Cao, Ming Chang Hu, Qiong Ding, Dongmei Lu, Sarah Elhadi, Massimo Attanasio, Shan Shan Wang, Chongyu Ren |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Nephrology Senescence medicine.medical_specialty Kidney Innate immune system business.industry Acute kidney injury Inflammation General Medicine medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Fibrosis 030220 oncology & carcinogenesis Internal medicine Cancer research Medicine medicine.symptom business Research Article Kidney disease |
| Zdroj: | JCI Insight. 4 |
| ISSN: | 2379-3708 |
| Popis: | Acute kidney injury (AKI) is a common clinical condition of growing incidence. Patients who suffer severe AKI have a higher risk of developing interstitial fibrosis, chronic kidney disease, and end-stage renal disease later in life. Cellular senescence is a persistent cell cycle arrest and altered gene expression pattern evoked by multiple stressors. The number of senescent cells increases with age and even in small numbers these cells can induce chronic inflammation and fibrosis; indeed, in multiple organs including kidneys, the accumulation of such cells is a hallmark of aging. We hypothesized that cellular senescence might be induced in the kidney after injury and that this might contribute to progressive organ fibrosis. Testing this hypothesis, we found that tubular epithelial cells (TECs) in mice senesce within a few days of kidney injury and that this response is mediated by epithelial Toll-like and interleukin 1 receptors (TLR/IL-1R) of the innate immune system. Epithelial cell–specific inhibition of innate immune signaling in mice by knockout of myeloid differentiation 88 (Myd88) reduced fibrosis as well as damage to kidney tubules, and also prevented the accumulation of senescent TECs. Importantly, although inactivation of Myd88 after injury ameliorated fibrosis, it did not reduce damage to the tubules. Selectively induced apoptosis of senescent cells by two different approaches only partially reduced kidney fibrosis, without ameliorating damage to the tubules. Our data reveal a cell-autonomous role for epithelial innate immunity in controlling TEC senescence after kidney injury, and additionally suggest that early therapeutic intervention is required for effective reduction of long-term sequelae of AKI. |
| Databáze: | OpenAIRE |
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