Elsevier

Kidney International

Volume 97, Issue 6, June 2020, Pages 1219-1229
Kidney International

Basic Research
IL-17C has a pathogenic role in kidney ischemia/reperfusion injury

https://doi.org/10.1016/j.kint.2020.01.015Get rights and content

Cytokines are necessary to trigger the inflammatory response in kidney ischemia/reperfusion injury. Interleukin-17C (IL-17C), a unique member of the IL-17 family, is a cytokine produced by epithelial cells implicated in host defense and autoimmune diseases. However, little is known about the role of IL-17C in acute kidney injury. We investigated this and found that IL-17C was significantly increased in kidney biopsies of patients and mice with acute kidney injury. Exposure to hypoxia induced upregulation of IL-17C in kidney tubular epithelial cells. To further investigate the role of IL-17C, kidney ischemia/reperfusion injury was induced in mice. Inhibition of IL-17C action with a neutralizing antibody or IL-17 receptor E (IL-17RE) knockout attenuated tubular injury, kidney oxidative stress, and kidney inflammation. Mechanistically, both IL-17C neutralization and IL-17RE knockout attenuated TH17 activation and IL-17A expression in kidneys of mice with acute kidney injury. TNF-α and IL-1β, downstream cytokines of IL-17C, were also reduced in IL-17C antibody pretreated and IL-17RE knockout mice. Additionally, IL-17C knockdown with siRNA decreased hypoxia-induced inflammation in kidney tubular cells and silencing IL-17RE abrogated the effects of IL-17C in kidney tubular cells. Thus, IL-17C may participate in the inflammatory response of acute kidney injury and inhibition of IL-17C or blockade of IL-17 RE may be a novel therapeutic strategy for the treatment of acute kidney injury.

Section snippets

Renal IL-17C was increased in human beings with AKI

To explore changes of renal IL-17C in AKI, IL-17C was measured by real-time quantitative polymerase chain reaction and immunohistochemistry. In a group of patients with AKI, renal IL-17C mRNA levels were increased significantly compared with control subjects (P < 0.05), as shown in Figure 1a. Furthermore, renal TNF-α and IL-1β were increased remarkably, consistent with IL-17C (Figure 1b and c). Consistently, renal IL-17C protein was expressed principally in renal tubular epithelial cells, and

Discussion

Inflammation has been identified as a key driving force in the pathophysiology of AKI. Renal tubular epithelial cells are extremely vulnerable to intrinsic oxidative stress because of their structure and function, particularly during the reperfusion phase of IRI.25 Necrotic cells release damage-associated molecules, which can activate resident kidney cells and immune effector cells, thus triggering an immune response.26 Proinflammatory and anti-inflammatory mediators released by activated

Human kidney biopsy samples

The use of human medical information and kidney samples was approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. This research was performed in accordance with the World Medical Association Declaration of Helsinki, and all subjects provided written informed consent. Subjects diagnosed with AKI and control subjects diagnosed with no obvious kidney pathology were enrolled and clinical data were recorded as described previously.42 AKI was diagnosed

Disclosure

All the authors declared no competing interests.

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81770741).

Author Contributions

FW designed and led the study; FW and YL drafted the manuscript; YL, JY, XL, GZ, YK, ZL, and RW performed the experiments; FW, FZ, NW, and TX performed data analysis; and TX and YQ provided reagents and technical support.

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