Canonical Wnt/β-catenin Signaling Mediates Transforming Growth Factor-β1-driven Podocyte Injury and Proteinuria

Overview

Journal Kidney Int

Publisher Elsevier

Specialty Nephrology

Date 2011 Aug 12

PMID 21832980

Citations 81

Authors

Dan Wang

Chunsun Dai

Yingjian Li

Youhua Liu

Affiliations

Soon will be listed here.

Abstract

Transforming growth factor-β1 (TGF-β1) upregulation occurs in virtually all chronic kidney diseases and is associated with podocyte injury and proteinuria; however, the mechanisms contributing to this in vivo are ambiguous. In vitro, incubation of podocytes with TGF-β1 induced Wnt1 expression, β-catenin activation, and stimulated the expression of Wnt/β-catenin downstream target genes. Ectopic expression of Wnt1 or β-catenin mimicked TGF-β1, induced Snail1, and suppressed nephrin expression. The Wnt antagonist, Dickkopf-1, blocked TGF-β1-induced β-catenin activation, Snail1 induction, and nephrin suppression. In vivo, ectopic expression of TGF-β1 induced Wnt1 expression, activated β-catenin, and upregulated Wnt target genes such as Snail1, MMP-7, MMP-9, desmin, Fsp1, and PAI-1 in mouse glomeruli, leading to podocyte injury and albuminuria. Consistently, concomitant expression of Dickkopf-1 gene abolished β-catenin activation, inhibited TGF-β1-triggered Wnt target gene expression, and mitigated albuminuria. Thus, canonical Wnt/β-catenin signaling mediates TGF-β1-driven podocyte injury and proteinuria. These studies suggest that Wnt/β-catenin signaling may be exploited as a therapeutic target for the treatment of proteinuric kidney diseases.

Citing Articles

UDA-seq: universal droplet microfluidics-based combinatorial indexing for massive-scale multimodal single-cell sequencing.

Li Y, Huang Z, Xu L, Fan Y, Ping J, Li G Nat Methods. 2025; .

PMID: 39833568 DOI: 10.1038/s41592-024-02586-y.

The Pathogenesis of Nephrotic Syndrome: A Perspective from B Cells.

Zhu S, Zhang J, Gao L, Ye Q, Mao J Kidney Dis (Basel). 2024; 10(6):531-544.

PMID: 39664337 PMC: 11631018. DOI: 10.1159/000540511.

Roles of macrophages in lupus nephritis.

Cheng Y, Liu L, Ye Y, He Y, Hu W, Ke H Front Pharmacol. 2024; 15:1477708.

PMID: 39611168 PMC: 11602334. DOI: 10.3389/fphar.2024.1477708.

Matrix metalloproteinases in kidney homeostasis and diseases: an update.

Tan R, Liu Y Am J Physiol Renal Physiol. 2024; 327(6):F967-F984.

PMID: 39361724 PMC: 11687849. DOI: 10.1152/ajprenal.00179.2024.

Scutellarin ameliorates diabetic nephropathy via TGF-β1 signaling pathway.

Huang B, Han R, Tan H, Zhu W, Li Y, Jiang F Nat Prod Bioprospect. 2024; 14(1):25.

PMID: 38656633 PMC: 11043297. DOI: 10.1007/s13659-024-00446-y.

References

Wang D, Li Y, Wu C, Liu Y . PINCH1 is transcriptional regulator in podocytes that interacts with WT1 and represses podocalyxin expression. PLoS One. 2011; 6(2):e17048. PMC: 3044754. DOI: 10.1371/journal.pone.0017048. View

Carroll T, Park J, Hayashi S, Majumdar A, McMahon A . Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell. 2005; 9(2):283-92. DOI: 10.1016/j.devcel.2005.05.016. View

Ten Berge D, Koole W, Fuerer C, Fish M, Eroglu E, Nusse R . Wnt signaling mediates self-organization and axis formation in embryoid bodies. Cell Stem Cell. 2008; 3(5):508-18. PMC: 2683270. DOI: 10.1016/j.stem.2008.09.013. View

Yamaguchi Y, Iwano M, Suzuki D, Nakatani K, Kimura K, Harada K . Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am J Kidney Dis. 2009; 54(4):653-64. DOI: 10.1053/j.ajkd.2009.05.009. View

Gerke P, Sellin L, Kretz O, Petraschka D, Zentgraf H, Benzing T . NEPH2 is located at the glomerular slit diaphragm, interacts with nephrin and is cleaved from podocytes by metalloproteinases. J Am Soc Nephrol. 2005; 16(6):1693-702. DOI: 10.1681/ASN.2004060439. View

Schnaper H, Jandeska S, Runyan C, Hubchak S, Basu R, Curley J . TGF-beta signal transduction in chronic kidney disease. Front Biosci (Landmark Ed). 2009; 14(7):2448-65. PMC: 4367189. DOI: 10.2741/3389. View

He W, Dai C, Li Y, Zeng G, Monga S, Liu Y . Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol. 2009; 20(4):765-76. PMC: 2663839. DOI: 10.1681/ASN.2008060566. View

Vincent T, Neve E, Johnson J, Kukalev A, Rojo F, Albanell J . A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009; 11(8):943-50. PMC: 3769970. DOI: 10.1038/ncb1905. View

Takano Y, Yamauchi K, Hiramatsu N, Kasai A, Hayakawa K, Yokouchi M . Recovery and maintenance of nephrin expression in cultured podocytes and identification of HGF as a repressor of nephrin. Am J Physiol Renal Physiol. 2007; 292(5):F1573-82. DOI: 10.1152/ajprenal.00423.2006. View

10.

Clevers H . Wnt/beta-catenin signaling in development and disease. Cell. 2006; 127(3):469-80. DOI: 10.1016/j.cell.2006.10.018. View

11.

Wu D, Bitzer M, Ju W, Mundel P, Bottinger E . TGF-beta concentration specifies differential signaling profiles of growth arrest/differentiation and apoptosis in podocytes. J Am Soc Nephrol. 2005; 16(11):3211-21. DOI: 10.1681/ASN.2004121055. View

12.

Schiffer M, Bitzer M, Roberts I, Kopp J, Ten Dijke P, Mundel P . Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest. 2001; 108(6):807-16. PMC: 200928. DOI: 10.1172/JCI12367. View

13.

Chang H, Gao F, Guillou F, Taketo M, Huff V, Behringer R . Wt1 negatively regulates beta-catenin signaling during testis development. Development. 2008; 135(10):1875-85. PMC: 4038296. DOI: 10.1242/dev.018572. View

14.

Bottinger E, Bitzer M . TGF-beta signaling in renal disease. J Am Soc Nephrol. 2002; 13(10):2600-10. DOI: 10.1097/01.asn.0000033611.79556.ae. View

15.

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

16.

Kim M, Yoon S, Bollig F, Kitagaki J, Hur W, Whye N . A novel Wilms tumor 1 (WT1) target gene negatively regulates the WNT signaling pathway. J Biol Chem. 2010; 285(19):14585-93. PMC: 2863207. DOI: 10.1074/jbc.M109.094334. View

17.

Li Y, Tan X, Dai C, Stolz D, Wang D, Liu Y . Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis. J Am Soc Nephrol. 2009; 20(9):1907-18. PMC: 2736781. DOI: 10.1681/ASN.2008090930. View

18.

Angers S, Moon R . Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009; 10(7):468-77. DOI: 10.1038/nrm2717. View

19.

Heikkila E, Juhila J, Lassila M, Messing M, Perala N, Lehtonen E . beta-Catenin mediates adriamycin-induced albuminuria and podocyte injury in adult mouse kidneys. Nephrol Dial Transplant. 2010; 25(8):2437-46. DOI: 10.1093/ndt/gfq076. View

20.

Hovanes K, Li T, Munguia J, Truong T, Milovanovic T, Marsh J . Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet. 2001; 28(1):53-7. DOI: 10.1038/ng0501-53. View