Calmodulin-dependent Protein Kinase II/cAMP Response Element-binding Protein/Wnt/β-Catenin Signaling Cascade Regulates Angiotensin II-induced Podocyte Injury and Albuminuria

Jiang, Lei; Xu, Lingling; Song, Yuxian; Li, Jianzhong; Mao, Junhua; Zhao, Allan Z.; He, Weichun; Yang, Junwei; Dai, Chunsun

doi:10.1074/jbc.m113.460394

Cited by 44 publications

(44 citation statements)

References 56 publications

(61 reference statements)

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“…7N and O). Of note, it was recently demonstrated that WNT5A-mediated, calcium-activated calmodulin kinase (Ca 2ϩ /CAMKII), with several signaling intermediates, plays a crucial role in immune cell functions (33)(34)(35). Therefore, we investigated the involvement of the WNT5A-Ca 2ϩ /CAMKII axis in the dectin-1-mediated signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

Trinath

Holla

Mahadik

et al. 2014

Molecular and Cellular Biology

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Macrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLRinduced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of ␤-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A. Subsequently, WNT5A-responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1␤, and tumor necrosis factor alpha (TNF-␣). In vivo activation of dectin-1 with pathogenic fungi or ligand resulted in an increased bacterial burden of Mycobacteria, Klebsiella, Staphylococcus, or Escherichia, with a concomitant decrease in TLR-triggered proinflammatory cytokines. All together, our study establishes a new role for dectin-1-responsive inhibitory mechanisms employed by virulent fungi to limit the proinflammatory environment of the host.

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Section: Resultsmentioning

confidence: 99%

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

Trinath

Holla

Mahadik

et al. 2014

Molecular and Cellular Biology

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“…This finding is in harmony with earlier observations that many pathogenic cues, such as Wnt, TGF-b, integrin-linked kinase, angiotensin II, and high glucose, induce, either directly or indirectly, b-catenin activation. 7,15,42,43 This study shows that b-catenin could trigger podocyte dedifferentiation/injury by multiple mechanisms. It targets WT1 for ubiquitin-mediated degradation.…”

Section: Discussionmentioning

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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“…Jiang et al reported that blocking of Wnt signaling prevents angiotensin II-induced nephropathy in mice. 43 He et al further showed that paricalcitol prevents doxorubicininduced nephropathy by suppressing podocyte Wnt/b-catenin activation. 11 Tzou et al reported that systemic injection of monoclonal antibody against Wnt receptor attenuates kidney damage in genetically insulin-deficient Akita mice.…”

Section: Discussionmentioning

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

Journal of the American Society of Nephrology

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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

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Calmodulin-dependent Protein Kinase II/cAMP Response Element-binding Protein/Wnt/β-Catenin Signaling Cascade Regulates Angiotensin II-induced Podocyte Injury and Albuminuria

Cited by 44 publications

References 56 publications

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

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

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

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