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Tenascin-C protects against acute kidney injury by recruiting Wnt ligands.

ABSTRACT: The development of acute kidney injury (AKI) is a complex process involving tubular, inflammatory, and vascular components, but less is known about the role of the interstitial microenvironment. We have previously shown that the extracellular matrix glycoprotein tenascin-C (TNC) is induced in fibrotic kidneys. In mouse models of AKI induced by ischemia-reperfusion injury (IRI) or cisplatin, TNC was induced de novo in the injured sites and localized to the renal interstitium. The circulating level of TNC protein was also elevated in AKI patients after cardiac surgery. Knockdown of TNC by shRNA in vivo aggravated AKI after ischemic or toxic injury. This effect was associated with reduced renal ?-catenin expression, suggesting an impact on Wnt signaling. In vitro, TNC protected tubular epithelial cells against apoptosis and augmented Wnt1-mediated ?-catenin activation. Co-immunoprecipitation revealed that TNC physically interacts with Wnt ligands. Furthermore, a TNC-enriched kidney tissue scaffold prepared from IRI mice was able to recruit and concentrate Wnt ligands from the surrounding milieu ex vivo. The ability to recruit Wnt ligands in this ex vivo model diminished after TNC depletion. These studies indicate that TNC is specifically induced at sites of injury and recruits Wnt ligands, thereby creating a favorable microenvironment for tubular repair and regeneration after AKI.

SUBMITTER: Chen S

PROVIDER: S-EPMC6320278 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Tenascin-C protects against acute kidney injury by recruiting Wnt ligands.

Chen Shuangqin S Fu Haiyan H Wu Songzhao S Zhu Wenjuan W Liao Jinlin J Hong Xue X Miao Jinhua J Luo Congwei C Wang Yongping Y Hou Fan Fan FF Zhou Lili L Liu Youhua Y

Kidney international 20181106 1

The development of acute kidney injury (AKI) is a complex process involving tubular, inflammatory, and vascular components, but less is known about the role of the interstitial microenvironment. We have previously shown that the extracellular matrix glycoprotein tenascin-C (TNC) is induced in fibrotic kidneys. In mouse models of AKI induced by ischemia-reperfusion injury (IRI) or cisplatin, TNC was induced de novo in the injured sites and localized to the renal interstitium. The circulating leve ...[more]

PMID: 30409456

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Project description:BackgroundInterleukin-17C (IL-17C), a member of the IL-17 cytokine family, plays a pathogenic role in kidney diseases. Our previous studies have shown that pre-administration of IL-17C neutralizing antibody attenuated acute kidney injury (AKI, a common acute inflammation associated renal disease). In this study, we explored whether post-ischemia reperfusion (IR) of IL-17C blockade has therapeutic effects on AKI and whether IL-17C is involved in the pathogenesis of diabetic nephropathy (DN), a major type of chronic inflammation-associated kidney disease.Methods12-week-old male C57BL/6JGpt mice were treated with IL-17C neutralizing antibody or normal IgG control antibody at 3 h after reperfusion. Renal injury, inflammation, and oxidative stress were assessed. Additionally, we examined renal IL-17C expression in patients with DN and db/db mice and evaluated albuminuria, mesangial matrix accumulation and podocyte loss in db/db mice with IL-17C neutralization. Knockdown of NF-κB p65 using siRNA, and blocking Hypoxia-inducible factor-1α (HIF-1α) using YC-1 in mice and HIF-1α Decoy in HK2 cells were investigated to explore the possible signaling pathway involved in IL-17C regulation.FindingsWe found that delayed IL-17C neutralization had similar reno-protective effects on renal ischemia-reperfusion injury (IRI). Additionally, renal IL-17C expression was increased in patients with DN and db/db mice, while IL-17C blockade significantly attenuated DN, accompanied with blunted albuminuria, mesangial matrix accumulation, and podocyte loss. Moreover, IL-17C neutralization significantly repressed the expression of downstream pro-inflammatory cytokines, inflammatory cell infiltration, and Th17/IL-17A activation both in mice with renal IRI and DN. Mechanistical studies demonstrated that hypoxia or high glucose-induced IL-17C up-regulation was predominantly mediated by NF-κB pathway.InterpretationIL-17C participates in the pathogenesis of AKI and DN and inhibition of IL-17C shows potential as a therapeutic strategy for AKI and DN.FundingThe National Natural Science Foundation of China (81770741, 81700601 and 81870504).

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Tenascin-C protects against acute kidney injury by recruiting Wnt ligands.

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Tenascin-C protects against acute kidney injury by recruiting Wnt ligands.

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