Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

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222

Activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. However, current anti-RAS therapy only has limited efficacy, partly because of compensatory upregulation of renin expression. Therefore, a treatment strategy to simultaneously target multiple RAS genes is necessary to achieve greater efficacy. By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor ( Extensive studies over the last several decades have established that activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. 1-3 RAS consists of several key components, including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1), and angiotensin II type 2 receptor (AT2). Many studies indicate that, after kidney injury, intrarenal RAS is markedly activated because of concurrent upregulation of multiple RAS genes. 4,5 RAS activation contributes to kidney and cardiovascular injury through a range of mechanisms. In addition to regulating BP and hemodynamics, 6,7 angiotensin II, the principal and active mediator of RAS, activates TGF-b1 and NF-kB signaling and directly promotes renal inflammation and fibrosis. 8-10 Studies using both genetic and pharmacologic approaches have confirmed the relevance and importance of RAS activation in the development and progression of CKD and cardiovascular disease. However, current anti-RAS therapy using ACE inhibitors (ACEIs) or angiotensin II receptor

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Multiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/β-Catenin Signaling

Zhou

Li²,

Hao³

et al. 2015

197

222

“…11 Tzou et al reported that systemic injection of monoclonal antibody against Wnt receptor attenuates kidney damage in genetically insulin-deficient Akita mice. 12 However, not all of the experiments targeting Wnt-signaling inhibition were successful in treating DKD. An endogenous Wnt receptor antagonist DKK1 was thought to be a potential pharmacologic target for podocytopathy, but systemic DKK1 injection accelerated mesangial matrix accumulation in DKD.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] As a developmental signaling pathway, the Wnt/b-catenin system is essentially silenced in differentiated podocytes, but activated Wnt/b-catenin signaling has been found in various types of proteinuric kidney disease, [9][10][11] particularly in DKD. 10,12,13 Wnt/b-catenin is a key element of podocyte dysfunction by downregulating nephrin via a Snail-dependent mechanism. 10 Target inhibition of podocyte Wnt signaling does not alter kidney microstructure and function but prevents podocytopathy in doxorubicin-induced nephropathy.…”

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confidence: 99%

Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease

Huang

Tarng

et al. 2015

Diabetic kidney disease (DKD) is a microvascular complication that leads to kidney dysfunction and ESRD, but the underlying mechanisms remain unclear. Podocyte Wnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/b-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-induced DKD model in FHL2 gene-knockout mice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-b1, activated FHL2 protein and Wnt/b-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigated the podocyte dedifferentiation caused by activated Wnt/b-catenin signaling under Wnt-On, but not under Wnt-Off, conditions. Diabetic FHL2 +/+ mice developed markedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2 +/+ mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with diabetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both structural and functional protein-protein interactions with b-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/b-catenin-induced podocytopathy. 26: 3072-3084, 201526: 3072-3084, . doi: 10.1681 Diabetic kidney disease (DKD) is the leading cause of ESRD, affecting 10%-40% of diabetic patients, and the cost of RRT remains a large economic burden for the health care system. Proteinuria is a major and primary clinical aspect of DKD and causes tubulointerstitial lesions that lead to renal dysfunction. 1 Reducing proteinuria may therefore be a principal therapeutic target to improve renal outcome in patients with DKD. However, the pathophysiologic mechanism of DKD is multifactorial, and some patients develop treatment-resistant proteinuria that results in ESRD despite intensive BP and glycemia control. Thus, identification of major DKD mechanisms and development of new therapeutic options are needed. Glomerular epithelial cells, also called podocytes, are predominantly responsible for maintaining the glomerular filtration barrier. Podocytes are highly specialized, terminally differentiated cells that cannot proliferate. 2 Recently, hyperactive podocyte J Am Soc Nephrol

“…[11][12][13] Extensive studies have shown aberrant activation of b-catenin in glomerular podocytes in a range of animal models of proteinuric CKD and human biopsies from patients with various kidney disorders, such as FSGS, diabetic nephropathy, and IgA nephropathy. 7,14,15 Consistently, either genetic ablation of b-catenin in a podocyte-specific fashion or pharmacologic inhibition of b-catenin signaling protects mice against podocyte dysfunction and proteinuria after injury. 7,10,16 These studies suggest that dysregulated activation of b-catenin signaling could be a common mechanism leading to podocyte dysfunction and proteinuria.…”

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confidence: 89%

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

Zhou

Li²,

He³

et al. 2015

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.