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 β-catenin expression, suggesting an impact on Wnt signaling. In vitro, TNC protected tubular epithelial cells against apoptosis and augmented Wnt1-mediated β-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.

How to sharpen a novel sword from AKI basic research

“…5 In this study, renal fibrosis was induced by 2 different models of unilateral ureteral obstruction and renal ischemia-reperfusion injury (with animals killed at day 10). As the authors pointed out in the present study, 4 TNC seems to be protective in AKI but detrimental in chronic kidney disease (CKD). The same authors also reported a similar result regarding Wnt/ b-catenin signaling.…”

“…TNC binds to extracellular matrix structural proteins and cell surface receptors, including the epidermal growth factor receptor and integrins, and activates several different downstream pathways, thereby modulating cell adhesion, spreading, migration, and proliferation. In this issue of Kidney International, Chen and colleagues 4 report a protective role of TNC against AKI. In vivo experiments using animal models of ischemia-reperfusion injury (with the animals killed at 30 hours) and cisplatin injection with short hairpin RNA-mediated knockdown of TNC both demonstrated that TNC induction in the renal interstitium was protective against AKI.…”

“…For TNC, a cisplatin injection model was used in addition to the renal ischemia-reperfusion injury model. 4 Further study using septic AKI models would provide greater face validity and would be more convincing of the potential of TNC as a novel drug target in AKI because sepsis is one of the most frequent causes of AKI in clinical settings. In addition, we need to consider not only kidney damage and loss of renal function but complex organ interactions in AKI between kidney and distant organs for improvement of outcomes of patients with AKI.…”

Human amniotic epithelial cells ameliorate kidney damage in ischemia-reperfusion mouse model of acute kidney injury

“…It was found that in normal kidney tenascin expression was limited to the medullary interstitium [ 44 ]. Chen et al reported that Tenascin-C (TNC), a member of the tenascin family, was specifically induced at sites of injury and recruited Wnt ligands, thereby creating a favorable microenvironment for tubular repair and regeneration after ischemia reperfusion-induced AKI [ 45 ]. Thus, it would be interesting to explore the in vivo role of TNXB on kidney regeneration in IRI models, leading to an elucidation of the molecular mechanism of hAECs therapy for IRI-AKI.…”

Human amniotic epithelial cells improve kidney repair in ischemia-reperfusion mouse model of acute kidney injury

“…Chen et.al. reported that Tenascin-C (TNC), a member of the tenascin family, was speci cally induced at sites of injury and recruited Wnt ligands, thereby creating a favorable microenvironment for tubular repair and regeneration after ischemia reperfusion-induced AKI [41]. Thus, it would be interesting to explore the in vivo role of TNXB on kidney regeneration in IRI models, leading to an elucidation of the molecular mechanism of hAECs therapy for AKI.…”