Matrix Metalloproteinase-7 as a Surrogate Marker Predicts Renal Wnt/β-Catenin Activity in CKD

He, Weichun; Tan, Roderick J.; Li, Yingjian; Wang, Dan; Nie, Jing; Hou, Fan Fan; Liu, Youhua

doi:10.1681/asn.2011050490

Cited by 134 publications

(176 citation statements)

References 45 publications

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“…18,19 However, chronic activation of this signaling seems to be detrimental, leading to development and progression of CKD. This notion is consistent with copious reports that Wnt/ b-catenin controls a battery of fibrogenic genes, such as Snail1, 15 plasminogen activator inhibitor-1 (PAI-1), 20 matrix metalloproteinase-7 (MMP-7), 21 fibroblast-specific protein 1 (Fsp1), 22 and multiple components of the renin-angiotensin system. 23,24 On the basis of these observations, it is conceivable to speculate that an early and transient activation of Wnt/ b-catenin after AKI may be renoprotective by facilitating tubular repair and regeneration, whereas sustained activation of the same signaling could promote AKI to CKD progression.…”

supporting

confidence: 89%

“…Furthermore, sustained activation of Wnt/b-catenin in severe AKI will cause an exaggerated induction of several key target genes, such as Snail1, PAI-1, MMP-7, Fsp1, and renin-angiotensin system genes ( Figures 5 and 6), all of which are relevant to the progression of CKD. 15,20,21,23 The importance of sustained Wnt signaling in driving AKI to CKD progression is also substantiated by in vivo expression of Wnt1, the prototype of Wnt ligands that is highly induced after IRI (Figures 2 and 3), or inhibiting Wnt/b-catenin signaling by using a small molecule inhibitor ICG-001. 34,43,44 Notably, we selected to manipulate Wnt/b-catenin at 5 days after IRI (Figures 4 and 7), a time point that extends beyond the initial injury and early repair/ regeneration phases after AKI, to assess the potential role of Wnt signaling in modulating AKI to CKD progression.…”

Section: Discussionmentioning

confidence: 95%

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

Lin

Zhou²,

Tan

et al. 2015

JASN

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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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supporting

confidence: 89%

Section: Discussionmentioning

confidence: 95%

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

Lin

Zhou²,

Tan

et al. 2015

JASN

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202

214

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“…16 Interestingly, multiple RAS genes are novel targets of Wnt/b-catenin signaling, and blockade of b-catenin signaling by a small-molecule inhibitor is able to inhibit RAS and ameliorate kidney injury. 12 In harmony with this notion, renal b-catenin and its downstream target proteins such as Snail1, PAI-1, and MMP-7 are upregulated in diseased kidneys, 23,28,31,51,52 which is concurrent with RAS activation. Therefore, Wnt/b-catenin presumably functions as a mediator in coupling Klotho depletion with RAS activation in various CKD including aging-related nephropathy.…”

Section: Klotho Inhibits Rasmentioning

confidence: 92%

“…28 Antibodies used were as follows: goat polyclonal anti-Klotho (AF1819; R&D Systems, Minneapolis, MN), goat polyclonal anti-AGT (sc-7419; Santa Cruz Biotechnology, Santa Cruz, CA), goat polyclonal anti-renin sc-27320; Santa Cruz Biotechnology), rabbit monoclonal anti-ACE (ab75762; Abcam, Cambridge, MA), rabbit polyclonal anti-AT1 receptor (ab15552; Millipore, Billerica, MA), rabbit polyclonal anti-b-catenin (ab15180; Abcam), rabbit polyclonal anti-FSP-1(S100A4) (A5114; Dako, Carpinteria, CA), mouse monoclonal antiea-SMA (A2547; Sigma-Aldrich, St. Louis, MO), rabbit polyclonal antieTGFb1 (sc-146; Santa Cruz Biotechnology), and rabbit polyclonal antieMMP-7 (GTX104658; GeneTex, Irvine, CA). After incubation with primary antibodies at 4 C overnight, the slides were then stained with horseradish peroxidaseeconjugated secondary antibody (Jackson ImmunoResearch Laboratories, West Grove, PA).…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

Zhou

Miao

et al. 2015

The American Journal of Pathology

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133

117

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Loss of Klotho and activation of the renin-angiotensin system (RAS) are common pathological findings in chronic kidney diseases. However, whether these two events are intricately connected is poorly understood. We hypothesized that Klotho might protect kidneys by targeted inhibition of RAS activation in diseased kidneys. To test this hypothesis, mouse models of remnant kidney, as well as adriamycin nephropathy and unilateral ureteral obstruction, were utilized. At 6 weeks after 5/6 nephrectomy, kidney injury was evident, characterized by elevated albuminuria and serum creatinine levels, and excessive deposition of interstitial matrix proteins. These lesions were accompanied by loss of renal Klotho expression, up-regulation of RAS components, and development of hypertension. In vivo expression of exogenous Klotho through hydrodynamic-based gene delivery abolished the induction of multiple RAS proteins, including angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor, and normalized blood pressure. Klotho also inhibited b-catenin activation and ameliorated renal fibrotic lesions. Similar results were obtained in mouse models of adriamycin and obstructive nephropathy. In cultured kidney tubular epithelial cells, Klotho dose-dependently blocked Wnt1-triggered RAS activation. Taken together, these results demonstrate that Klotho exerts its renal protection by targeted inhibition of RAS, a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders. Chronic kidney disease (CKD) is increasingly recognized as a major public health problem, because it affects about 10% to 13% of the adult population worldwide.1e3 Among many risk factors for developing CKD, aging is an independent and strong predictor for progressive renal insufficiency. 4 The elderly population also tends to develop hypertension and cardiovascular disease, characteristic features consistent with the activation of the renin-angiotensin system (RAS). 5,6 These observations suggest that aging, CKD, and RAS activation might be intimately linked. However, the molecular details behind these connections are not fully understood.RAS consists of several key components, including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), and angiotensin II type I and type II receptors (AT1 and AT2, respectively).7e9 Two main enzymes in this system, renin and ACE, lead to the formation of angiotensin II, the principal active peptide of RAS, which mediates both blood pressureedependent and eindependent kidney damage in CKD. Several factors can induce RAS activation, such as reactive oxygen species, hyperglycemia, and albumin. 10,11 We recently found that all RAS genes contain T cell factor/ lymphoid enhancer-binding factor binding sites in their promoter regions and are directly regulated by canonical Wnt/ b-catenin signaling.12 These results have established that bcatenin is a master regulator controlling the expression of all RAS components in the kidneys.

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“…Meanwhile, b-catenin target genes, such as plasminogen activator inhibitor-1 (PAI-1), 28 Snail1, 7 and a-smooth muscle actin (a-SMA), were markedly induced ( Figure 2B). Quantitative real-time RT-PCR (qRT-PCR) show that matrix metalloproteinase-7 (MMP-7), another direct downstream target gene of b-catenin, 29 was also induced in a time-dependent manner (data not shown). Immunostaining confirmed the downregulation of podocyte-specific proteins, such as nephrin, podocalyxin, and synaptopodin after ADR injury, which was accompanied by de novo expression of MMP-7, PAI-1, fibroblast-specific protein-1 (FSP-1), and a-SMA specifically in glomerular podocytes ( Figure 2H).…”

Section: Loss Of Wt1 Is Associated With B-catenin Activation and Podomentioning

confidence: 99%

Mutual Antagonism of Wilms’ Tumor 1 and β-Catenin Dictates Podocyte Health and Disease

Zhou

Li²,

He³

et al. 2015

Journal of the American Society of Nephrology

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Activation of b-catenin, the intracellular mediator of canonical Wnt signaling, has a critical role in mediating podocyte injury and proteinuria. However, the underlying mechanisms remain poorly understood. Here, we show that b-catenin triggers ubiquitin-mediated protein degradation of Wilms' tumor 1 (WT1) and functionally antagonizes its action. In mice injected with adriamycin, WT1 protein was progressively lost in glomerular podocytes at 1, 3, and 5 weeks after injection. Notably, loss of WT1 apparently did not result from podocyte depletion but was closely associated with upregulation of b-catenin. This change in WT1/ b-catenin ratio was accompanied by loss of podocyte-specific nephrin, podocalyxin, and synaptopodin and acquisition of mesenchymal markers Snail1, a-smooth muscle actin, and fibroblast-specific protein 1. In vitro, overexpression of b-catenin induced WT1 protein degradation through the ubiquitin proteasomal pathway, which was blocked by MG-132. WT1 and b-catenin also competed for binding to common transcriptional coactivator CREB-binding protein and mutually repressed the expression of their respective target genes. In glomerular miniorgan culture, activation of b-catenin by Wnt3a repressed WT1 and its target gene expression. In vivo, blockade of Wnt/b-catenin signaling by endogenous antagonist Klotho induced WT1 and restored podocyte integrity in adriamycin nephropathy. These results show that b-catenin specifically targets WT1 for ubiquitin-mediated degradation, leading to podocyte dedifferentiation and mesenchymal transition. Our data also suggest that WT1 and b-catenin have opposing roles in podocyte biology, and that the ratio of their expression levels dictates the state of podocyte health and disease in vivo.

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Matrix Metalloproteinase-7 as a Surrogate Marker Predicts Renal Wnt/β-Catenin Activity in CKD

Cited by 134 publications

References 45 publications

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

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

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

Mutual Antagonism of Wilms’ Tumor 1 and β-Catenin Dictates Podocyte Health and Disease

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