Expression and Function of the Developmental Gene Wnt-4 during Experimental Acute Renal Failure in Rats

Terada, Yoshio; Tanaka, Hiroyuki; Okado, Tomokazu; Shimamura, Haruko; Inoshita, Seiji; Kuwahara, Michio; Sasaki, Sei

doi:10.1097/01.asn.0000060577.94532.06

Cited by 148 publications

(116 citation statements)

References 31 publications

(38 reference statements)

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“…Transient activation of Wnt/b-catenin is associated with moderate AKI after 20-minute IRI (Figure 2). Given the fact that Wnt signaling promotes tubular cell survival by inhibiting apoptosis and augmenting cell proliferation, [40][41][42] such a transient activation of Wnt/b-catenin in the early stage of AKI seems beneficial by minimizing the injury and promoting repair and regeneration. Consistent with this view, genetic knockout of the b-catenin gene in tubule-specific fashion is shown to aggravate kidney injury after both ischemic and nephrotoxic insults.…”

Section: Discussionmentioning

confidence: 99%

Sustained Activation of Wnt/β-Catenin Signaling Drives AKI to CKD Progression

Lin

Zhou²,

Tan

et al. 2015

JASN

202

214

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AKI is increasingly recognized as a major risk factor for progression to CKD. However, the factors governing AKI to CKD progression are poorly understood. In this study, we investigated this issue using moderate (20 minutes) and severe (30 minutes) ischemia/reperfusion injury (IRI) in mice. Moderate IRI led to acute kidney failure and transient Wnt/b-catenin activation, which was followed by the restoration of kidney morphology and function. However, severe IRI resulted in sustained and exaggerated Wnt/ b-catenin activation, which was accompanied by development of renal fibrotic lesions characterized by interstitial myofibroblast activation and excessive extracellular matrix deposition. To assess the role of sustained Wnt/b-catenin signaling in mediating AKI to CKD progression, we manipulated this signaling by overexpression of Wnt ligand or pharmacologic inhibition of b-catenin. In vivo, overexpression of Wnt1 at 5 days after IRI induced b-catenin activation and accelerated AKI to CKD progression. Conversely, blockade of Wnt/b-catenin by small molecule inhibitor ICG-001 at this point hindered AKI to CKD progression. In vitro, Wnt ligands induced renal interstitial fibroblast activation and promoted fibronectin expression. However, activated fibroblasts readily reverted to a quiescent phenotype after Wnt ligands were removed, suggesting that fibroblast activation requires persistent Wnt signaling. These results indicate that sustained, but not transient, activation of Wnt/b-catenin signaling has a decisive role in driving AKI to CKD progression. 27: 172727: -174027: , 201627: . doi: 10.1681 AKI is responsible for about 2 million deaths each year worldwide, and its incidence is rising. 1-3 AKI is increasingly common in critically ill patients, and those patients with severe AKI requiring dialysis have a mortality rate of .50%. In contrast to the traditional belief that survivors of AKI tend to fully recover renal function, there is growing evidence that patients who survive an episode of AKI will have a significant risk of developing progressive CKD and even ESRD. 1,2,4 Evidence is also mounting that the severity and frequency of AKI seem to be closely correlated with poor patient long-term outcome, 5,6 suggesting that AKI may be a predictive and causative factor for subsequent development of CKD. In this context, delineation of the underlying mechanisms governing the different courses of long-term outcome after AKI will not only shed new light on understanding the pathophysiology of AKI-CKD progression but also is instrumental in designing rational strategies for therapeutic intervention. J Am Soc NephrolWnt/b-catenin is a developmental signaling pathway that plays an essential role in regulating

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Section: Discussionmentioning

confidence: 99%

Sustained Activation of Wnt/β-Catenin Signaling Drives AKI to CKD Progression

Lin

Zhou²,

Tan

et al. 2015

JASN

202

214

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“…Rats were euthanized at 0, 3,6,12,24,48, and 72 h after surgery (n ϭ 5 rats/group). The left kidney was rapidly removed and processed for histological evaluation, protein extraction, and RNA extraction, as previously described (38,40). Control animals were age-and weightmatched rats that received a sham operation without clamping of the renal arteries and were euthanized at 0 and 12 h (n ϭ 5 rats/group).…”

Section: Induction Of Akimentioning

confidence: 99%

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Imamura

Urushido

Hamada

et al. 2013

American Journal of Physiology-Renal Physiology

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175

125

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Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1␣ and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stressinduced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1␣-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1␣-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.Bcl-2/adenovirus E1B 19 kDa-interacting protein-3; acute kidney injury; autophagy; mitophagy; sestrin-2 ISCHEMIA is the leading cause of acute kidney injury (AKI) in the adult population. Prominent morphological features of ischemic AKI include effacement and loss of the proximal tubule brush border, patchy loss of tubular cells, focal areas of proximal tubular dilation, and increased apoptosis (9). The mechanisms that dictate the survival or death of renal cells under oxidative stress must be more completely understood before novel therapeutic strategies for the treatment of ischemic AKI can be explored. Proximal renal tubular cells have high rates of ATP consumption and are very sensitive to hypoxia; thus, mitochondrial damage is one of the most important factors in determining the survival of these cells (1,43).Autophagy is one of the cellular processes that protect cells from genotoxic stress, oxidative stress, accumulation of misfolded proteins, and nutrient deprivation. We (20) have previously reported results from a study of autophagy in a mouse model of AKI. Autophagy plays roles in the pathogenesis of many diseases, and, in kidney disease, both beneficial and detrimental effects of autophagy have been reported (19 -22). Our understanding of autophagy has expanded greatly in recent years, largely due to the identification...

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“…Tissue regeneration is thought to recapitulate developmental paradigms in various organs. Several developmental genes indispensable for kidney organogenesis, such as Pax-2 (10, 15), Wnt4 (30), and LIF (37), have been demonstrated to be reactivated in regenerating tubules after injury, thus suggesting the similarity of kidney development and repair.…”

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confidence: 99%