Dickkopf-1 Promotes Hyperglycemia-induced Accumulation of Mesangial Matrix and Renal Dysfunction

Overview

Journal J Am Soc Nephrol

Specialty Nephrology

Date 2009 Dec 19

PMID 20019166

Citations 55

Authors

Chun-Liang Lin

Jeng-Yi Wang

Jih-Yang Ko

Yu-Ting Huang

Yu-Hsia Kuo

Feng-Sheng Wang

Affiliations

Soon will be listed here.

Abstract

Wnt/beta-catenin signaling mediates renal fibrosis in several model systems including diabetic nephropathy. Dickkopf-1 (DKK-1) is an endogenous inhibitor of Wnt/beta-catenin signaling, but whether DKK-1 modulates diabetic nephropathy is unknown. Here, we studied whether DKK-1 participates in high glucose (HG)-induced expression of profibrotic factors and renal damage. In vitro, HG increased expression of DKK1, receptor Kremen-2, TGF-beta1, and fibronectin in mesangial cells. Loss and gain of DKK1 function modulated HG-mediated c-Jun, TGF-beta1, and fibronectin expression. DKK1 mediated HG-induced phosphorylation of Ser45-beta-catenin and reduction of nuclear beta-catenin levels, but not phosphorylation of ERK kinase. Wnt3a protein and the beta-catenin (Delta45) mutation increased nuclear beta-catenin but abrogated HG-induced DKK1 and fibronectin expression. Exogenous DKK1 antisense oligonucleotide attenuated the increase in both serum DKK1 and urinary protein excretion in streptozotocin-induced diabetic rats. Knocking down DKK1 inhibited mesangial expression of TGF-beta1 and fibronectin and reduced both the glomerular volume and deposition of mesangial matrix in diabetic kidneys. Taken together, DKK1 mediates HG-induced destabilization of beta-catenin and matrix accumulation in mesangial cells. Knocking down DKK1 prevents diabetes-induced renal dysfunction and microstructure deterioration, suggesting that inhibition of DKK1offers therapeutic potential for diabetic nephropathy.

Citing Articles

Synergistic modulation of endoplasmic reticulum stress pathway, oxidative DNA damage and apoptosis by β-amyrin and metformin in mitigating hyperglycemia-induced renal damage using adult zebrafish model.

Roohi T, Krishna K, Shakeel F BMC Pharmacol Toxicol. 2024; 25(1):66.

PMID: 39334288 PMC: 11430224. DOI: 10.1186/s40360-024-00797-9.

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease.

Ko J, Wang F, Lian W, Yang F, Chen J, Huang P Mol Med. 2024; 30(1):66.

PMID: 38773377 PMC: 11106911. DOI: 10.1186/s10020-024-00838-3.

Podocyte-targeted therapies - progress and future directions.

Meliambro K, He J, Campbell K Nat Rev Nephrol. 2024; 20(10):643-658.

PMID: 38724717 DOI: 10.1038/s41581-024-00843-z.

Pathomechanisms of Diabetic Kidney Disease.

Sinha S, Nicholas S J Clin Med. 2023; 12(23).

PMID: 38068400 PMC: 10707303. DOI: 10.3390/jcm12237349.

Ascorbate protects human kidney organoids from damage induced by cell-free hemoglobin.

Bejoy J, Farry J, Qian E, Dearing C, Ware L, Bastarache J Dis Model Mech. 2023; 16(12).

PMID: 37942584 PMC: 10695115. DOI: 10.1242/dmm.050342.

References

Canalis E, Giustina A, Bilezikian J . Mechanisms of anabolic therapies for osteoporosis. N Engl J Med. 2007; 357(9):905-16. DOI: 10.1056/NEJMra067395. View

Wang K, Zhang Y, Li X, Chen L, Wang H, Wu J . Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism. J Biol Chem. 2008; 283(34):23371-5. PMC: 2516984. DOI: 10.1074/jbc.M802376200. View

Rudnicki M, Eder S, Perco P, Enrich J, Scheiber K, Koppelstatter C . Gene expression profiles of human proximal tubular epithelial cells in proteinuric nephropathies. Kidney Int. 2006; 71(4):325-35. DOI: 10.1038/sj.ki.5002043. View

Nateri A, Spencer-Dene B, Behrens A . Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature. 2005; 437(7056):281-5. DOI: 10.1038/nature03914. View

Shao J, Cheng S, Pingsterhaus J, Charlton-Kachigian N, Loewy A, Towler D . Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005; 115(5):1210-20. PMC: 1077175. DOI: 10.1172/JCI24140. View

Avvisato C, Yang X, Shah S, Hoxter B, Li W, Gaynor R . Mechanical force modulates global gene expression and beta-catenin signaling in colon cancer cells. J Cell Sci. 2007; 120(Pt 15):2672-82. DOI: 10.1242/jcs.03476. View

Mimeault M, Mehta P, Hauke R, Batra S . Functions of normal and malignant prostatic stem/progenitor cells in tissue regeneration and cancer progression and novel targeting therapies. Endocr Rev. 2008; 29(2):234-52. PMC: 2528844. DOI: 10.1210/er.2007-0040. View

Urakami S, Shiina H, Enokida H, Hirata H, Kawamoto K, Kawakami T . Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA. Clin Cancer Res. 2006; 12(23):6989-97. DOI: 10.1158/1078-0432.CCR-06-1194. View

Peruzzi B, Bottaro D . Beta-catenin signaling: linking renal cell carcinoma and polycystic kidney disease. Cell Cycle. 2007; 5(24):2839-41. DOI: 10.4161/cc.5.24.3581. View

10.

Verani R, Cappuccio I, Spinsanti P, Gradini R, Caruso A, Magnotti M . Expression of the Wnt inhibitor Dickkopf-1 is required for the induction of neural markers in mouse embryonic stem cells differentiating in response to retinoic acid. J Neurochem. 2006; 100(1):242-50. DOI: 10.1111/j.1471-4159.2006.04207.x. View

11.

Twells R, Mein C, Payne F, Veijola R, Gilbey M, Bright M . Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes. Hum Genet. 2003; 113(2):99-105. DOI: 10.1007/s00439-003-0940-6. View

12.

Namkoong C, Kim M, Jang P, Han S, Park H, Koh E . Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes. 2004; 54(1):63-8. DOI: 10.2337/diabetes.54.1.63. View

13.

Marks J, Carvou N, Debnam E, Srai S, Unwin R . Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J Physiol. 2003; 553(Pt 1):137-45. PMC: 2343472. DOI: 10.1113/jphysiol.2003.046268. View

14.

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

15.

Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B . The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003; 349(26):2483-94. DOI: 10.1056/NEJMoa030847. View

16.

Kwack M, Sung Y, Chung E, Im S, Ahn J, Kim M . Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes. J Invest Dermatol. 2007; 128(2):262-9. DOI: 10.1038/sj.jid.5700999. View

17.

Trevant B, Gaur T, Hussain S, Symons J, Komm B, Bodine P . Expression of secreted frizzled related protein 1, a Wnt antagonist, in brain, kidney, and skeleton is dispensable for normal embryonic development. J Cell Physiol. 2008; 217(1):113-26. PMC: 3992714. DOI: 10.1002/jcp.21482. View

18.

Furlong F, Crean J, Thornton L, OLeary R, Murphy M, Martin F . Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose. Am J Physiol Renal Physiol. 2007; 292(6):F1691-700. DOI: 10.1152/ajprenal.00342.2006. View

19.

Huang H, He X . Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol. 2008; 20(2):119-25. PMC: 2390924. DOI: 10.1016/j.ceb.2008.01.009. View

20.

Masszi A, Fan L, Rosivall L, McCulloch C, Rotstein O, Mucsi I . Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. Am J Pathol. 2004; 165(6):1955-67. PMC: 1618715. DOI: 10.1016/s0002-9440(10)63247-6. View