Wnt Agonist Decreases Tissue Damage and Improves Renal Function After Ischemia-Reperfusion

Kuncewitch, Michael; Yang, Weng Lang; Nicastro, J.; Coppa, Gene F.; Wang, P.

doi:10.1016/j.jss.2012.10.652

Cited by 7 publications

(6 citation statements)

References 22 publications

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“…In line with this view, Wnt/b-catenin is activated in both ischemic and nephrotoxic AKI, and tubule-specific deletion of b-catenin aggravates kidney injury, 32 whereas Wnt agonist reduces tissue damage and improves renal function after IRI. 35 AKI is characterized by tubular cell apoptosis and renal inflammation, followed by the proliferation of the survived tubular cells, leading to repair and recovery. 34,36,37 Cell apoptosis is regulated by 2 distinct pathways: the extrinsic, death receptor-dependent and intrinsic, mitochondria-dependent routes.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

Zhou

Zhu

et al. 2019

Kidney International

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Matrix metalloproteinase-7 (MMP-7) is a secreted endopeptidase that degrades a broad range of substrates. Recent studies have identified MMP-7 as an early biomarker to predict severe acute kidney injury (AKI) and poor outcomes after cardiac surgery; however, the role of MMP-7 in the pathogenesis of AKI is unknown. In this study, we investigated the expression of MMP-7 and the impact of MMP-7 deficiency in several models of AKI. MMP-7 was induced in renal tubules following ischemia/ reperfusion injury or cisplatin administration, and in folic acid-induced AKI. MMP-7 knockout mice experienced higher mortality, elevated serum creatinine, and more severe histologic lesions after ischemic or toxic insults. Tubular apoptosis and interstitial inflammation were more prominent in MMP-7 knockout kidneys. These histologic changes were accompanied by increased expression of FasL and other components of the extrinsic apoptotic pathway, as well as increased expression of pro-inflammatory chemokines. In a rescue experiment, exogenous MMP-7 ameliorated kidney injury in MMP-7 knockout mice after ischemia/ reperfusion. In vitro, MMP-7 protected tubular epithelial cells against apoptosis by directly degrading FasL. In isolated tubules ex vivo, MMP-7 promoted cell proliferation by degrading E-cadherin and thereby liberating b-catenin, priming renal tubules for regeneration. Taken together, these results suggest that induction of MMP-7 is protective in AKI by degrading FasL and mobilizing b-catenin, thereby priming kidney tubules for survival and regeneration.Matrix metalloproteinase-7 (MMP-7) is an early and valuable biomarker for predicting severe AKI and poor outcomes in patients after cardiac surgery. The present study indicates that induction of endogenous MMP-7 is protective in AKI by priming kidney tubules to survival and regeneration. These results suggest that other urinary biomarkers of the early phase of AKI manifest an initial attempt of the kidney to protect against injury and to promote repair after AKI. Whether infusion of exogenous MMP-7 can protect kidneys against AKI in patients warrants further investigation. www.kidney-international.org b a s i c r e s e a r c h Kidney International (2019) 95, 1167-1180

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

Zhou

Zhu

et al. 2019

Kidney International

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“…Also, the inactivation of b-catenin by small interfering RNA increased the ischemia-induced infarct volume in rats (39). Additionally, the Wnt/b-catenin pathway also plays a critical role in the protective effects of preconditioning against lethal ischemic injury in the heart (40), kidneys (41), liver (42), and c, d) and HPC groups (e, f), and 168 h after reperfusion of tGCI groups (g, h) and HPC groups (i, j), respectively. Scale bars, 250 mm (a, c, e, g, i) and 25 mm (b, d, f, h, j).…”

Section: Discussionmentioning

confidence: 99%

Hypoxic postconditioning activates the Wnt/β‐catenin pathway and protects against transient global cerebral ischemia through Dkk1 Inhibition and GSK‐3β inactivation

et al. 2019

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The Wingless/Int (Wnt)/β‐catenin pathway plays an essential role in cell survival. Although post‐conditioning with 8% oxygen can alleviate transient global cerebral ischemia (tGCI)‐induced neuronal damage in hippocampal CA1 subregion in adult rats as demonstrated by our previous studies, little is understood about the role of Wnt/β‐catenin pathway in hypoxic postconditioning (HPC)‐induced neuroprotection. This study tried to investigate the involvement of Wnt/β‐catenin pathway in HPC‐induced neuroprotection against tGCI and explore the underlying molecular mechanism thereof. We observed that HPC elevated nuclear β‐catenin level as well as increased Wnt3a and decreased Dickkopf‐1 (Dkk1) expression in CA1 after tGCI. Accordingly, HPC enhanced the expression of survivin and reduced the ratio of B‐cell lymphoma/lewkmia‐2 (Bcl‐2)–associated X protein (Bax) to Bcl‐2 following reperfusion. Moreover, our study has shown that these effects of HPC were abolished by lentivirus‐mediated overexpression of Dkk1, and that the overexpression of Dkk1 completely reversed HPC‐induced neuroprotection. Furthermore, HPC suppressed the activity of glycogen synthase kinase‐3β (GSK‐3β) in CA1 after tGCI, and the inhibition of GSK‐3β activity with SB216763 increased the nuclear accumulation of β‐catenin, up‐regulated the expression of survivin, and reduced the ratio of Bax to Bcl‐2, thus preventing the delayed neuronal death after tGCI. Finally, the administration of LY294002, an inhibitor of PI3K, increased GSK‐3β activity and blocked nuclear β‐catenin accumulation, thereby decreasing survivin expression and elevating the Bax‐to‐Bcl‐2 ratio after HPC. These results suggest that activation of the Wnt/β‐catenin pathway through Dkk1 inhibition and PI3K/protein kinase B pathway–mediated GSK‐3β inactivation contributes to the neuroprotection of HPC against tGCI.—Zhan, L., Liu, D., Wen, H., Hu, J., Pang, T., Sun, W., Xu, E. Hypoxic postconditioning activates the Wnt/β‐catenin pathway and protects against transient global cerebral ischemia through Dkk1 inhibition and GSK‐3β inactivation. FASEB J. 33, 9291–9307 (2019). http://www.fasebj.org

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“…Five upregulated pathways in DCD grafts (RET, Alpha catenin, GMNN, SOX1 and SOX3) were associated with renal development and cell proliferation, and partly associate with the Wnt/β-catenin signaling pathways; [20][21][22][23][24] a pivotal pathway in kidney development, repair and regeneration. [25][26][27][28][29][30] The sixth upregulated pathway was the BRCA1 tumor suppressor pathway. BRCA1 is a key player in cellular repair through its role in DNA repair and cell cycle checkpoint activation.…”

Section: Discussionmentioning

confidence: 99%

The Neglectable Impact of Delayed Graft Function on Long-term Graft Survival in Kidneys Donated After Circulatory Death Associates With Superior Organ Resilience

et al. 2019

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Wnt Agonist Decreases Tissue Damage and Improves Renal Function After Ischemia-Reperfusion

Cited by 7 publications

References 22 publications

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

Hypoxic postconditioning activates the Wnt/β‐catenin pathway and protects against transient global cerebral ischemia through Dkk1 Inhibition and GSK‐3β inactivation

The Neglectable Impact of Delayed Graft Function on Long-term Graft Survival in Kidneys Donated After Circulatory Death Associates With Superior Organ Resilience

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