Journal article
Epithelial innate immunity mediates tubular cell senescence after kidney injury
JCI insight, Vol.4(2), e125490
01/24/2019
DOI: 10.1172/jci.insight.125490
PMCID: PMC6413792
PMID: 30674725
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.
Tubular cells innate immunity signaling controls spreading of cellular senescence, pericytes cell fate, and inflammation after kidney injury.
Details
- Title: Subtitle
- Epithelial innate immunity mediates tubular cell senescence after kidney injury
- Creators
- Heng Jin - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAYan Zhang - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAQiong Ding - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAShan Shan Wang - Zhongshan Hospital, Fudan University, Shanghai, ChinaPrerna Rastogi - Department of Pathology, University of Iowa, Iowa City, Iowa, USADao-Fu Dai - Department of Pathology, University of Iowa, Iowa City, Iowa, USADongmei Lu - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAMadison Purvis - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAChao Cao - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAAngela Wang - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USADingxiao Liu - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAChongyu Ren - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USASarah Elhadi - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAMing-Chang Hu - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAYanfen Chai - Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, ChinaDiana Zepeda-Orozco - Department of Pediatrics, University of Iowa, Iowa City, Iowa, USAJudith Campisi - The Buck Institute for Research on Aging, Novato, California, USAMassimo Attanasio - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.4(2), e125490
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.125490
- PMID
- 30674725
- PMCID
- PMC6413792
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- 1R01DK090326-01A1 / NIDDK
- Language
- English
- Date published
- 01/24/2019
- Academic Unit
- Epidemiology; Pathology; Iowa Neuroscience Institute; Radiation Oncology; Dental Research; Internal Medicine
- Record Identifier
- 9984047636502771
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