Epithelial innate immunity mediates tubular cell senescence after kidney injury

Jin, Heng; Zhang, Yan; Ding, Qiong; Wang, Shan Shan; Rastogi, Prerna; Dai, Dao Fu; Lu, Dongmei; Purvis, Madison; Cao, Chao; Wang, Angela Yee-Moon; Liu, Dingxiao; Ren, Cheng; El-Hadi, Sarah; Hu, Ming; Chai, Yifeng; Zepeda‐Orozco, Diana; Campisi, Judith; Attanasio, Massimo

doi:10.1172/jci.insight.125490

Cited by 85 publications

(85 citation statements)

References 58 publications

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“…Cell cycle arrest (as definition of senescence) in tubule epithelial cells causes renal fibrosis via the TLR/IL-1R pathway. However, inactivation of this pathway in myeloid differentiation (Myd88) knockout mice consequently reduced renal fibrosis but not damage of tubules after AKI [49].…”

Section: Discussionmentioning

confidence: 99%

“Point of no return” in unilateral renal ischemia reperfusion injury in mice

et al. 2020

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Background: In the past years evidence has been growing about the interconnection of chronic kidney disease and acute kidney injury. The underlying pathophysiological mechanisms remain unclear. We hypothesized, that a threshold ischemia time in unilateral ischemia/reperfusion injury sets an extent of ischemic tubule necrosis, which as "point of no return" leads to progressive injury. This progress is temporarily associated by increased markers of inflammation and results in fibrosis and atrophy of the ischemic kidney. Methods: Acute tubule necrosis was induced by unilateral ischemia/reperfusion injury in male C57BL/6 N mice with different ischemia times (15, 25, 35, and 45 min). At multiple time points between 15 min and 5 weeks we assessed gene expression of markers for injury, inflammation, and fibrosis, histologically the injury of tubules, cell death (TUNEL), macrophages, neutrophil influx and kidney atrophy. Results: Unilateral ischemia for 15 and 25 min induced upregulation of markers for injury after reperfusion for 24 h but no upregulation after 5 weeks. None of the markers for inflammation or fibrosis were upregulated after ischemia for 15 and 25 min at 24 h or 5 weeks on a gene expression level, except for Il-6. Ischemia for 35 and 45 min consistently induced upregulation of markers for inflammation, injury, and partially of fibrosis (Tgf-β1 and Col1a1) at 24 h and 5 weeks. The threshold ischemia time for persistent injury of 35 min induced a temporal association of markers for inflammation and injury with peaks between 6 h and 7 d along the course of 10 d. This ischemia time also induced persistent cell death (TUNEL) throughout observation for 5 weeks with a peak at 6 h and progressing kidney atrophy beginning 7 d after ischemia. Conclusions: This study confirms the evidence of a threshold extent of ischemic injury in which markers of injury, inflammation and fibrosis do not decline to baseline but remain upregulated assessed in long term outcome (5 weeks). Excess of this threshold as "point of no return" leads to persistent cell death and progressing atrophy and is characterized by a temporal association of markers for inflammation and injury.

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Section: Discussionmentioning

confidence: 99%

“Point of no return” in unilateral renal ischemia reperfusion injury in mice

et al. 2020

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“…To detect lysosomal β-Gal, the citric acid/sodium phosphate was at pH 4.0. For each cortical region, 10 consecutive fields at original magnification ×200 per section were selected for measurement (53). Signals were quantified by digital elaboration of microscopy images using ImageJ software (NIH, https://imagej.nih.gov/ij/).…”

Section: Methodsmentioning

confidence: 99%

Disruption of Robo2-Baiap2 integrated signaling drives cystic disease

Li¹,

Cui²,

Ma³

et al. 2019

JCI Insight

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“…Indeed, hallmarks of cellular senescence, such as nuclear expression of p16 INK4a , were found to be more pronounced in renal tubular cells than in other renal cell types during ageing ( Melk et al, 2004 ). Experimental models demonstrated that a variety of injuries could induce cellular senescence and subsequent fibrosis in renal tubular epithelial cells ( Jin et al, 2019 ). In the ageing kidney, the regenerative capability of renal tubular cells after acute insults significantly declines, concomitant with increased cell senescence and augmented SASP, which may impair renal tubular cell repopulation and promote fibrotic maladaptive renal repair, ultimately leading to an exacerbated AKI to CKD transition and accelerated kidney ageing ( Li and Wang, 2018 ; Luo et al, 2018 ).…”

Section: Cell Senescence In Renal Ageingmentioning

confidence: 99%

The ageing kidney: Molecular mechanisms and clinical implications

Fang

Gong

Haller

et al. 2020

Ageing Research Reviews

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As human life expectancy keeps increasing, ageing populations present a growing challenge for clinical practices. Human ageing is associated with molecular, structural, and functional changes in a variety of organ systems, including the kidney. During the ageing process, the kidney experiences progressive functional decline as well as macroscopic and microscopic histological alterations, which are accentuated by systemic comorbidities like hypertension and diabetes mellitus, or by preexisting or underlying kidney diseases. Although ageing per se does not cause kidney injury, physiologic changes associated with normal ageing processes are likely to impair the reparative capacity of the kidney and thus predispose older people to acute kidney disease, chronic kidney disease and other renal diseases. Mechanistically, cell senescence plays a key role in renal ageing, involving a number of cellular signaling mechanisms, many of which may be harnessed as interventional targets for slowing or even reversing kidney ageing. This review summarizes the clinical characteristics of renal ageing, highlights the latest progresses in deciphering the role of cell senescence in renal ageing, and envisages potential interventional strategies and novel therapeutic targets for preventing or improving renal ageing in the hope of maintaining long-term kidney health and function across the life course.

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Epithelial innate immunity mediates tubular cell senescence after kidney injury

Cited by 85 publications

References 58 publications

“Point of no return” in unilateral renal ischemia reperfusion injury in mice

“Point of no return” in unilateral renal ischemia reperfusion injury in mice

Disruption of Robo2-Baiap2 integrated signaling drives cystic disease

The ageing kidney: Molecular mechanisms and clinical implications

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