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Epithelial innate immunity mediates tubular cell senescence after kidney injury
Heng Jin, … , Judith Campisi, Massimo Attanasio
Heng Jin, … , Judith Campisi, Massimo Attanasio
Published January 24, 2019
Citation Information: JCI Insight. 2019;4(2):e125490. https://doi.org/10.1172/jci.insight.125490.
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Research Article Inflammation Nephrology

Epithelial innate immunity mediates tubular cell senescence after kidney injury

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Abstract

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.

Authors

Heng Jin, Yan Zhang, Qiong Ding, Shan Shan Wang, Prerna Rastogi, Dao-Fu Dai, Dongmei Lu, Madison Purvis, Chao Cao, Angela Wang, Dingxiao Liu, Chongyu Ren, Sarah Elhadi, Ming-Chang Hu, Yanfen Chai, Diana Zepeda-Orozco, Judith Campisi, Massimo Attanasio

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Figure 8

Epithelial cell–specific deletion of Myd88 after injury reduces fibrosis but does not protect from tubular damage.

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Epithelial cell–specific deletion of Myd88 after injury reduces fibrosis...
(A) Representative images of trichrome-stained kidneys at low (upper panels) and high (lower panels) magnification of KspCre-ERT2Myd88fl/fl mice compared with KspCre-ERT2Myd88+/+ controls 28 days after FA injury. Scale bars: 500 μm (upper) and 200 μm (lower). (B) Collagen/total protein content ratios and (C) real-time quantitative PCR of the collagen 1 mRNA levels in kidney cortexes of KspCre-ERT2Myd88fl/fl mice compared with controls 28 days after FA injury. (D) Representative immunofluorescence confocal images of KspCre-ERT2Myd88fl/fl mouse kidneys immunostained for the fibroblast marker FSP1 compared with controls 28 days after FA injury, and (E) corresponding quantification by digital image analysis. Scale bars: 20 μm. (F) Representative immunofluorescence confocal images of KspCre-ERT2Myd88fl/fl mouse kidneys immunostained for the myofibroblast marker α-SMA compared with controls 28 days after FA injury, and (G) corresponding quantification by digital image analysis. Scale bars: 20 μm. (H) Representative immunofluorescence confocal images of KspCre-ERT2Myd88fl/fl mouse kidneys immunostained for the macrophage marker F4/80 compared with controls 28 days after FA injury and (I) corresponding quantification by digital image analysis. Scale bars are 20 μm. (J) Representative images of PAS-stained kidneys at low (upper panels) and high (lower panels) magnification of KspCre-ERT2Myd88fl/fl mice compared with controls 28 days after FA injury. Scale bars: 500 μm (upper) and 200 μm (lower). (K) Tubular injury scores for KspCre-ERT2Myd88fl/fl mice compared with controls 28 days after FA injury. Experimental numbers of mice are reported in each panel. Data are presented as mean ± SD. P values were calculated using the 2-tailed Student’s t test.

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