|Year : 2015 | Volume
| Issue : 1 | Page : 19-22
Recent advances of Wnt signaling in kidney diseases
Mingqian Jiang1, Li Wang2, Aili Cao2, Peihao Yin2, Wen Peng1, Hao Wang1
1 Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
2 Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
|Date of Web Publication||23-Jan-2015|
Department of Nephrology, Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 LanXi Road, Shanghai - 200 062
Source of Support: This work was supported by General Medicine of Key Discipline Construction Project, State Administration of Traditional Chinese Medicine of the People’s Republic of China; Leading Academic Discipline Project of State Administration of Traditional Chinese Medicine of China, Talent Project of Integrative Medicine of Shanghai Municipal Health Bureau (ZYSNXD012-RC-ZXY); Key Medical Discipline Project of Shanghai Municipal Health Bureau (ZK2012A34); Independent Innovation Research Fund of Putuo District Science and Technology Committee (2012PTKW002) ; Budget Project of Shanghai Municipal Education Commission (2012JW71) and Putuo Hospital Fund (2013SR123I, 2013GQ007I). Confl ict of Interest: No., Conflict of Interest: None
Kidney diseases are a serious hazard to human health, and many different molecular signaling pathways are involved in the complex pathogenesis. Recently the Wnt signaling pathway, one of the most conserved intercellular signaling cascades, has been considered as an effective regulator in various kidney diseases, including ischemic kidney injury, glomerular diseases, diabetic nephropathy, interstitial fibrosis and cystic kidney diseases. Besides, more and more evidence have suggested that the altered Wnt signaling pathway is correlated with the pathological process of kidney diseases, which might offer a novel therapeutic strategy. Therefore, to enhance understanding, here we reviewed the major roles of Wnt signaling cascades and their roles in kidney diseases.
Keywords: Chronic kidney disease, diabetic nephropathy, renal fibrosis, Wnt signaling pathway
|How to cite this article:|
Jiang M, Wang L, Cao A, Yin P, Peng W, Wang H. Recent advances of Wnt signaling in kidney diseases. J Integr Nephrol Androl 2015;2:19-22
| Introduction|| |
An estimated 500 million people in this world are diagnosed with different kinds of kidney diseases. Chronic kidney disease has become yet another life-threatening illness after cardio- and cerebrovascular diseases, tumor, and diabetes. A major pattern and common feature of different kidney diseases is fibrosis of various degrees, which is also a crucial mechanism to kidney failure. The Wnt signaling pathway has an important role in fetus development and is involved in various physiological and pathological processes, including regulating cell differentiation, carcinogenesis, apoptosis, wound healing, and fibrosis. Recent studies have indicated that the activation and dysfunction of Wnt signaling is closely related to the pathogenesis and development of kidney fibrosis, diabetic nephropathy, polycystic kidney disease, and so forth. This article aims to review the research development of Wnt signaling in kidney diseases.
Overview of Wnt signaling
Wnt, a secreting glycoprotein rich in cysteine residue, is highly conservative during the entire evolution process and is expressed in many different kinds of tissue cells. The secreting glycoprotein of the Wnt family has 19 ligands, including Wnt 1, 2, 2b, 3, 3a, 4, 5a, 5b, 6, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11, and Wnt 16.  These ligands are typically linked with the extracellular cell matrix (ECM), with a temporal and spatial regulation pattern. , The Wnt protein has its typical paracrine and autocrine effects in terms of activating membrane receptors, the expression of which is a major initiating signal to activate downstream signaling.  The latest researches have revealed that the hydrophobic Wnts may transform to soluble proteins under certain conditions to effect on a farther distance,once Wnts reach the outside of the cell, they transform the insoluble membrane-attached proteins into long-range signaling molecules that can spread several cell diameters away from their source of production. In principle, these includes some different mechanisms to solubilize hydrophobic Wnts.Firstly, lipases could remove the lipid modifications and produce soluble proteins. Secondly, Wnts could be transferred from cell to cell at sites of cell contact. Thirdly, the lipid modifications of Wnts by lipid-binding proteins and could be shielded inside micelle-like aggregates. Moreover, experimental evidence exists that these mechanisms are indeed active in tissues and this still need to a future study. 
The canonical Wnt signaling
The canonical Wnt signaling begins with the activation of β-catenin. When lacking Wnt ligands, β-catenin combines with axin, glycogen synthase kinase-3beta (GSK-3β) and anaphase-promoting complex (APC) protein complex. Axin and APC are scaffolding proteins that promote the phosphorylation of β-catenin by GSK-3β. The highly effective ubiquitination of β-catenin lead to rapid degradation of protease by transducing homogeneous proteins with repeat sequences. The combination of Wnt protein and FZD receptor complex results in a cascade to inhibit the degradation of β-catenin, causing its accumulation inside the nucleus; on the other hand, the combination of β-catenin with TCF and/or LEF transcription factors regulates the Wnt target gene and its transcription process. Activation of the canonical Wnt signaling alters cell proliferation, differentiation and cell fate.  The outline of canonical Wnt/β-catenin is depicted in [Figure 1].
The non-canonical Wnt pathway
The non-canonical Wnt pathway includes Wnt-Ca 2+ and Wnt-JNK signaling pathways. Wnt promotes intracellular Ca 2+ release via the FZD family with the mediating effect of G protein. The release of Ca 2+ then activates two protein kinases, CamK-II and protein kinase C (PKC), thus inducing various cellular reactions. Because of the possible crucial role of Ca 2+ in activating CamK-II and PKC, it is referred to as Wnt-Ca 2+ non-canonical signaling.  Wnt-JNK signaling is mediated by GTPase RhoA, followed by activation of the Dsh protein DEP domain, a silent element in the canonical pathway, which further leads to activation of JNK (Jun N-terminal kinase). JNK is an intermediate component downstream of Wnt signaling. Once activated, JNK is transferred from the cytosol to the nucleus, and further combines with the transcription factor ATF2 and the amino terminal of c-jun and phosphorylates to further regulate the function of genes. 
| Wnt signaling and renal injury|| |
The physiological reaction and healing process are closely related, which are dominated by remodeling of tissue structure after functional recovery. The underlying reason is still unclear, and this process is only observed in adults. 
Progressive renal injury is closely related to glomerulosclerosis and interstitial fibrosis of the kidney. Fibrosis at this level serves as a major indicative factor for the prognosis of progressive renal injury. Inflammation and tissue remodeling are two generally accepted pathological changes in the process of fibrosis. In the acute phase of inflammation, immunological response typically leads to morphological and functional remodeling of damaged tissue. Apart from activating inflammatory leukocytes and endothelial cells, fibrosis also activates epithelial cells and fibroblasts.  Macrophages also play a crucial role in kidney fibrosis. With macrophage infiltration, Wnt2, Wnt5a and WNt7b are subsequently upregulated,  and the production of Wnt7b by macrophages may help to stimulate the repair and regeneration of kidney tissue. 
| Wnt signaling and kidney fibrosis|| |
Kidney fibrosis and atrophy are major intrinsic mechanism in the progressive development of kidney diseases and decrease in renal function. The rodent unilateral ureteral ligation model provides a rapid initiation of kidney fibrosis accompanied with massive leukocyte infiltration. In this model, the expressions of Wnt ligand, receptor and antagonist are expressed at different levels, which together maintain a dynamic balance for normal tissue.  After unilateral ureteral obstruction, the expression of the Wnt family (except Wnt5b, Wnt8b and Wnt9b) is markedly upregulated; meanwhile, most FZD receptors and Wnt antagonists are upregulated as well. Activation of the canonical Wnt signaling leads to accumulation of β-catenin on tubular epithelial cells to enhance expression of Wnt/β-catenin target genes.  Gene therapy can deliver DKK-1, a Wnt antagonist, that reduces accumulation of β-catenin and inhibits expression of Wnt/β-catenin target genes.
sFRP4, a soluble Wnt antagonist, plays a major role in unilateral ureteral obstruction model.  The expression of sFRP4 decreases in renal injury, and with the activation of the canonical Wnt signaling in tubular epithelial and interstitial cells follows aggravation of fibrosis. Peritoneal injection of recombinate sFRP4 leads to reduced β-catenin signal, decreased myofibroblasts, and relieved kidney fibrosis in adjacent tubular epithelial cells in the obstructed kidney; moreover, the increase of Wnt1 after obstruction leads to activation of β-catenin and upregulation of plasminogen activator inhibitor 1 (PAI-1), a downstream target cell. PAI-1 is closely related to the process of progressive kidney fibrosis and inflammation. 
| Wnt signaling and diabetic nephropathy|| |
One distinguished feature of diabetic nephropathy is elevated metabolism and excessive glucose production during signal transduction and subsequent increase of ECM, glomerular fibrosis, interstitial fibrosis, and ultimately end-stage renal disease. It is suggested that the disregulation of canonical Wnt/β-catenin is tightly relevant in the progression of diabetic nephropathy.  The Wnt/β-catenin pathway is also involved in the accumulation of ECM protein in diabetic nephropathy that is regulated by TGF-β-/smad. 
In in-vitro and in-vivo experiments of diabetic nephropathy, Wnt and cytosolic β-catenin in proximal tubular epithelial cells are upregulated, and connective tissue growth factor (CTGF) and fibronectin (FN) are also upregulated. It is suggested that in the diabetic nephropathy animal model, peritoneal injection of LRP5 and LRP6 antagonists inhibits the Wnt signaling pathway activation and reduces ECM synthesis, indicating a possible role of Wnt/β-catenin in the process of tubular interstitial fibrosis in diabetic nephropathy.  Additionally, Wnt4 is expressed initially in collective duct cells under a high glucose condition, but with the progression of the disease, Wnt is activated and appears in the interstitial zone,  indicating a potential effect of Wnt4 in the development of renal fibrosis in later stages of diabetic nephropathy. The underlying mechanism of Wnt/β-catenin and the joint regulating effect along with other cascade signaling pathways is still rather complicated and requires further investigation.
| Wnt signaling and ckd|| |
Alterations in Wnt signaling are relevant in chronic organ failure,  which may be achieved directly by overexpression of a Wnt ligand or activation of downstream channel proteins of the Wnt signaling cascade. The key genes in Wnt signaling is markedly upregulated in chronic kidney diseases, and these genes are involved in cell adhesion, proliferation, differentiation, polarization, migration, invasion, and so forth.  Doxorubicin induces activation of Wnt/β-catenin that inhibits the expression of nephrin and subsequent formation of proteinuria.  It is also suggested that in CKD stage 4 to 5 patients, the genetic expression of Wnt signaling in mononuclear blood cells is markedly elevated.  Mononuclear cells have a major effect in congenital immunity and post-infection immune response. Disregulation of mononuclear antigen presenting cell significantly increases the vulnerability of CKD patients to infection. Hence, some have proposed that most chronic kidney diseases are chronic and systemic inflammatory diseases that are mainly due to disorders of mononuclear cells. 
Upregulation of FZD4, Wnt5a, β-catenin and dvl1, as well as downregulation of phosphorylated GSK-3β suggest that the canonical Wnt signaling is involved in the progression of chronic kidney diseases.  The IL-6 level in CKD patient serum is markedly elevated, which is relevant in the formation of Wnt signaling proteins.  Wnt5a upregulates the expression of IL-6, which is a pro-inflammation factor.  In addition, in atherosclerosis patients, Wnt5a induces inflammation of endothelial cells.  Activation of Wnt/β-catenin signaling promotes adhesion of mononuclear cells onto endothelial cells and reduces its migration through the endothelium,  indicating a possible effect of such signaling pathway to the immunity of chronic kidney disease patients. Therefore, it is possible to improve the immunity of chronic kidney disease patients by regulating Wnt signaling.
In addition, in lupus nephritis, Wnt signaling is activated, accompanied by renal and serum DKK-1 upregulation. Wnt signaling participates in ECM formation, suggesting its potential regulating effect in glomerulonephritis. Studies have shown that in acute kidney injury animal model, mRNA and protein expression of Wnt4 in proximal tubule is markedly upregulated. Wnt/β-catenin signaling activates downstream TCF-1/LEF-1, which promotes cyst formation in polycystic kidney disease. 
| Conclusion|| |
To conclude, Wnt signaling has a very wide effect in regulating various kidney diseases, but the nature of Wnt signaling and its underlying mechanism in kidney diseases are not completely understood. This regulation effect and its interaction with other signaling pathways, the effect and significance of target gene activation, as well as the physiological effect of involved molecules require further verification. Due to the intimate relationship of Wnt signaling and kidney diseases, it would possibly be a promising method to treat kidney diseases and restore renal function by regulating the signal transduction of Wnt signaling. Wnt antagonists with different mechanisms and different targets provide novel options and ideas for further investigation and research.
| Acknowledgements|| |
This work was supported by General Medicine of Key Discipline Construction Project, State Administration of Traditional Chinese Medicine of the People's Republic of China; Leading Academic Discipline Project of State Administration of Traditional Chinese Medicine of China, Talent Project of Integrative Medicine of Shanghai Municipal Health Bureau (ZYSNXD012-RC-ZXY); Key Medical Discipline Project of Shanghai Municipal Health Bureau (ZK2012A34); Independent Innovation Research Fund of Putuo District Science and Technology Committee (2012PTKW002) ; Budget Project of Shanghai Municipal Education Commission (2012JW71) and Putuo Hospital Fund (2013SR123I, 2013GQ007I).
| References|| |
Chien AJ, Conrad WH, Moon RT. A Wnt survival guide: From flies to human disease. J Invest Dermatol 2009;129:1614-27.
Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998;14:59-88.
Lum L, Beachy PA. The Hedgehog response network: Sensors, switches, and routers. Science 2004;304:1755-9.
Kleber M, Sommer L. Wnt signaling and the regulation of stem cell function. Curr Opin Cell Biol 2004;16:681-7.
Port F, Basler K. Wnt trafficking: New insights into Wnt maturation, secretion and spreading. Traffic 2010;11:1265-71.
Coombs GS, Covey TM, Virshup DM. Wnt signaling in development, disease and translational medicine. Curr Drug Targets 2008;9:513-31.
De A. Wnt/Ca2+ signaling pathway: A brief overview. Acta Biochim Biophys Sin (Shanghai) 2011;43:745-56.
Pandur P, Maurus D, Kuhl M. Increasingly complex: New players enter the Wnt signaling network. Bioessays 2002;24:881-4.
Hewitson TD. Renal tubulointerstitial fibrosis: Common but never simple. Am J Physiol Renal Physiol 2009;296:F1239-44.
Nickeleit V, Andreoni K. Inflammatory cells in renal allografts. Front Biosci 2008;13:6202-13.
Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, et al
. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 2005;437:417-21.
Meuten T, Hickey A, Franklin K, Grossi B, Tobias J, Newman DR, et al
. WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis. Respir Res 2012;13:62.
He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y. Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol 2009;20:765-76.
Wang L, Chi YF, Yuan ZT, Zhou WC, Yin PH, Zhang XM, et al
. Astragaloside IV inhibits the up-regulation of Wnt/beta-catenin signaling in rats with unilateral ureteral obstruction. Cell Physiol Biochem 2014;33:1316-28.
Surendran K, Schiavi S, Hruska KA. Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J Am Soc Nephrol 2005;16:2373-84.
He W, Tan R, Dai C, Li Y, Wang D, Hao S, et al
. Plasminogen Activator Inhibitor-1 Is a Transcriptional Target of the Canonical Pathway of Wnt/ -Catenin Signaling. J Biol Chem 2010;285:24665-75.
Cohen CD, Lindenmeyer MT, Eichinger F, Hahn A, Seifert M, Moll AG, et al
. Improved elucidation of biological processes linked to diabetic nephropathy by single probe-based microarray data analysis. PLoS One 2008;3:e2937.
Ho C, Lee PH, Hsu YC, Wang FS, Huang YT, Lin CL. Sustained Wnt/beta-catenin signaling rescues high glucose induction of transforming growth factor-beta1-mediated renal fibrosis. Am J Med Sci 2012;344:374-82.
Zhou T, He X, Cheng R, Zhang B, Zhang RR, Chen Y, et al
. Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy. Diabetologia 2012;55:255-66.
Surendran K, McCaul SP, Simon TC. A role for Wnt-4 in renal fibrosis. Am J Physiol Renal Physiol 2002;282:F431-41.
von Toerne C, Schmidt C, Adams J, Kiss E, Bedke J, Porubsky S, et al
. Wnt pathway regulation in chronic renal allograft damage. Am J Transplant 2009;9:2223-39.
George SJ. Wnt pathway: A new role in regulation of inflammation. Arterioscler Thromb Vasc Biol 2008;28:400-2.
Wang D, Dai C, Li Y, Liu Y. Canonical Wnt/beta-catenin signaling mediates transforming growth factor-beta1-driven podocyte injury and proteinuria. Kidney Int 2011;80:1159-69.
Al-Chaqmaqchi HA, Moshfegh A, Dadfar E, Paulsson J, Hassan M, Jacobson SH, et al
. Activation of Wnt/beta-catenin pathway in monocytes derived from chronic kidney disease patients. PLoS One 2013;8:e68937.
Ledo N, Ko YA, Park AS, Kang HM, Han SY, Choi P, et al
. Functional Genomic Annotation of Genetic Risk Loci Highlights Inflammation and Epithelial Biology Networks in CKD. J Am Soc Nephrol 2014 26:1-26.
de Oliveira RB, Graciolli FG, dos Reis LM, Cancela AL, Cuppari L, Canziani ME, et al
. Disturbances of Wnt/beta-catenin pathway and energy metabolism in early CKD: Effect of phosphate binders. Nephrol Dial Transplant 2013;28:2510-7.
Katoh M, Katoh M. Transcriptional mechanisms of WNT5A based on NF-kappaB, Hedgehog, TGFbeta, and Notch signaling cascades. Int J Mol Med 2009;23:763-9.
Lehtonen A, Ahlfors H, Veckman V, Miettinen M, Lahesmaa R, Julkunen I. Gene expression profiling during differentiation of human monocytes to macrophages or dendritic cells. J Leukoc Biol 2007;82:710-20.
Kim J, Kim J, Kim DW, Ha Y, Ihm MH, Kim H, et al
. Wnt5a induces endothelial inflammation via beta-catenin-independent signaling. J Immunol 2010;185:1274-82.
Tickenbrock L, Schwäble J, Strey A, Sargin B, Hehn S, Baas M, et al
. Wnt signaling regulates transendothelial migration of monocytes. J Leukoc Biol 2006;79:1306-13.
Wuebken A, Schmidt-Ott KM. WNT/beta-catenin signaling in polycystic kidney disease. Kidney Int 2011;80:135-8.