Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Canonical Wnt signaling in the kidney in different hypertension models

Abstract

There is a close relationship between the kidney and blood pressure. On the one hand, kidney dysfunction causes an increase in blood pressure; on the other hand, high blood pressure causes kidney dysfunction. Wnt/β-catenin signaling is a key pathway that regulates various cellular processes and tissue homeostasis and is also involved in damage and repair processes. In healthy organs, Wnt/β-catenin signaling is muted, but it is activated in pathological states. The purpose of the present study was to immunohistochemically evaluate and compare the expression of WNT4, WNT10A, Fzd8, β-catenin, and GSK-3ß (glycogen synthase kinase 3β) in the kidneys of rats with essential arterial hypertension (SHR), renal–renal hypertension (2K1C), and DOCA-salt-induced hypertension. The study was performed on five male WKY rats, seven SHRs, and twenty-four (n = 24) young male Wistar rats. The main results showed that during hypertension, there are changes in Wnt/β-catenin signaling in the kidneys of rats, and the severity of these changes depends on the type of hypertension. This study is the first to assess the levels of some elements of the canonical Wnt/β-catenin signal transduction pathway in various types of arterial hypertension by immunohistochemistry and may form the basis for further molecular and functional studies of this pathway in hypertension.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Data availability

All relevant data are contained within the paper.

References

  1. 1.

    Sternlicht H, Bakris GL. The kidney in hypertension. Med Clin North Am. 2017;101:207–17.

    PubMed  Article  Google Scholar 

  2. 2.

    Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American heart association councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention. Hypertension. 2003;42:1050–65.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Adler S, Huang H. Oxidant stress in kidneys of spontaneously hypertensive rats involves both oxidase overexpression and loss of extracellular superoxide dismutase. Am J Physiol Ren Physiol. 2004;287:F907–13.

    CAS  Article  Google Scholar 

  4. 4.

    Zhou XJ, Vaziri ND, Zhang J, Wang HW, Wang XQ. Association of renal injury with nitric oxide deficiency in aged SHR: prevention by hypertension control with AT1 blockade. Kidney Int. 2002;62:914–21.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Elks CM, Mariappan N, Haque M, Guggilam A, Majid DS, Francis J. Chronic NF-{kappa}B blockade reduces cytosolic and mitochondrial oxidative stress and attenuates renal injury and hypertension in SHR. Am J Physiol Ren Physiol. 2009;296:F298–305.

    CAS  Article  Google Scholar 

  6. 6.

    Zhan CD, Sindhu RK, Pang J, Ehdaie A, Vaziri ND. Superoxide dismutase, catalase and glutathione peroxidase in the spontaneously hypertensive rat kidney: effect of antioxidant-rich diet. J Hypertens. 2004;22:2025–33.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Kobori H, Ozawa Y, Suzaki Y, Nishiyama A. Enhanced intrarenal angiotensinogen contributes to early renal injury in spontaneously hypertensive rats. J Am Soc Nephrol. 2005;16:2073–80.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Mai M, Geiger H, Hilgers KF, Veelken R, Mann JF, Dämmrich J, et al. Early interstitial changes in hypertension-induced renal injury. Hypertension. 1993;22:754–65.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Kobayashi S, Ishida A, Moriya H, Mori N, Fukuda T, Takamura T. Angiotensin II receptor blockade limits kidney injury in two-kidney, one-clip Goldblatt hypertensive rats with special reference to phenotypic changes. J Lab Clin Med. 1999;133:134–43.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Gómez GI, Velarde V. Boldine improves kidney damage in the Goldblatt 2K1C model avoiding the increase in TGF-β. Int J Mol Sci. 2018;19:1864.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  11. 11.

    Welch WJ, Mendonca M, Aslam S, Wilcox CS. Roles of oxidative stress and AT1 receptors in renal hemodynamics and oxygenation in the postclipped 2K,1C kidney. Hypertension. 2003;41:692–6.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Hilgers KF, Hartner A, Porst M, Mai M, Wittmann M, Hugo C, et al. Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury. Kidney Int. 2000;58:2408–19.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Oishi T, Ogura T, Yamauchi T, Harada K, Ota Z. Effect of renin-angiotensin inhibition on glomerular injuries in DOCA-salt hypertensive rats. Regul Pept. 1996;62:89–95.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Seifi B, Kadkhodaee M, Karimian SM, Zahmatkesh M, Shams S, Bakhshi E. Reduction of kidney damage by supplementation of vitamins C and E in rats with deoxycorticosterone-salt-induced hypertension. Iran J Kidney Dis. 2009;3:197–202.

    PubMed  Google Scholar 

  15. 15.

    Klanke B, Cordasic N, Hartner A, Schmieder RE, Veelken R, Hilgers KF. Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension. Nephrol Dial Transpl. 2008;23:3456–63.

    CAS  Article  Google Scholar 

  16. 16.

    Schupp N, Kolkhof P, Queisser N, Gärtner S, Schmid U, Kretschmer A, et al. Mineralocorticoid receptor-mediated DNA damage in kidneys of DOCA-salt hypertensive rats. FASEB J. 2011;25:968–78.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Gross V, Lippoldt A, Luft FC. Pressure diuresis and natriuresis in DOCA-salt mice. Kidney Int. 1997;52:1364–8.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Wang X, Johnson AC, Sasser JM, Williams JM, Solberg Woods LC, Garrett MR. Spontaneous one-kidney rats are more susceptible to develop hypertension by DOCA-NaCl and subsequent kidney injury compared with uninephrectomized rats. Am J Physiol Ren Physiol. 2016;310:F1054–64.

    CAS  Article  Google Scholar 

  19. 19.

    Abou Ziki MD, Mani A. Wnt signaling, a novel pathway regulating blood pressure? State of the art review. Atherosclerosis. 2017;262:171–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Zhou L, Chen X, Lu M, Wu Q, Yuan Q, Hu C, et al. Wnt/β-catenin links oxidative stress to podocyte injury and proteinuria. Kidney Int. 2019;95:830–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Dai C, Stolz DB, Kiss LP, Monga SP, Holzman LB, Liu Y. Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol. 2009;20:1997–2008.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Kato H, Gruenwald A, Suh JH, Miner JH, Barisoni-Thomas L, Taketo MM, et al. Wnt/β-catenin pathway in podocytes integrates cell adhesion, differentiation, and survival. J Biol Chem. 2011;286:26003–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Cox SN, Sallustio F, Serino G, Pontrelli P, Verrienti R, Pesce F, et al. Altered modulation of WNT-beta-catenin and PI3K/Akt pathways in IgA nephropathy. Kidney Int. 2010;78:396–407.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Wang XD, Huang XF, Yan QR, Bao CD. Aberrant activation of the WNT/β-catenin signaling pathway in lupus nephritis. PLoS One. 2014;9:e84852.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Zhou D, Li Y, Lin L, Zhou L, Igarashi P, Liu Y. Tubule-specific ablation of endogenous β-catenin aggravates acute kidney injury in mice. Kidney Int. 2012;82:537–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Terada Y, Tanaka H, Okado T, Shimamura H, Inoshita S, Kuwahara M, et al. Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats. J Am Soc Nephrol. 2003;14:1223–33.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Zhao Y, Wang C, Hong X, Miao J, Liao Y, Hou FF, et al. Wnt/β-catenin signaling mediates both heart and kidney injury in type 2 cardiorenal syndrome. Kidney Int. 2019;95:815–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Xiao L, Xu B, Zhou L, Tan RJ, Zhou D, Fu H, et al. Wnt/β-catenin regulates blood pressure and kidney injury in rats. Biochim Biophys Acta Mol Basis Dis. 2019;1865:1313–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    He W, Kang YS, Dai C, Liu Y. Blockade of Wnt/β-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury. J Am Soc Nephrol. 2011;22:90–103.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Surendran K, McCaul SP, Simon TC. A role for Wnt-4 in renal fibrosis. Am J Physiol Ren Physiol. 2002;282:F431–41.

    CAS  Article  Google Scholar 

  32. 32.

    Lin X, Zha Y, Zeng XZ, Dong R, Wang QH, Wang DT. Role of the Wnt/β-catenin signaling pathway in inducing apoptosis and renal fibrosis in 5/6-nephrectomized rats. Mol Med Rep. 2017;15:3575–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    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.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Zhou D, Tan RJ, Fu H, Liu Y. Wnt/β-catenin signaling in kidney injury and repair: a double-edged sword. Lab Invest. 2016;96:156–67.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Cui R, Chen X, Peng L, Ma J, Zhu D, Li T, et al. Multiple mechanisms in renal artery stenosis-induced renal interstitial fibrosis. Nephron Exp Nephrol. 2014;128:57–66.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Cuevas CA, Tapia-Rojas C, Cespedes C, Inestrosa NC, Vio CP. β-catenin-dependent signaling pathway contributes to renal fibrosis in hypertensive. Biomed Res Int. 2015;2015:726012.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Goldblatt H, Lynch J, Hanzal RF, Summerville WW. Studies on experimental hypertension: I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med. 1934;59:347–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Kasacka I, Piotrowska Ż, Niezgoda M, Lewandowska A, Łebkowski W. Ageing-related changes in the levels of β-catenin, CacyBP/SIP, galectin-3 and immunoproteasome subunit LMP7 in the heart of men. PLoS One. 2020;15:e0229462.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Zhou L, Li Y, Hao S, Zhou D, Tan RJ, Nie J, et al. Multiple genes of the renin-angiotensin system are novel targets of Wnt/β-catenin signaling. J Am Soc Nephrol. 2015;26:107–20.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Clozel JP, Müller RK, Roux S, Fischli W, Baumgartner HR. Influence of the status of the renin-angiotensin system on the effect of cilazapril on neointima formation after vascular injury in rats. Circulation. 1993;88:1222–7.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Wong DWL, Yiu WH, Chan KW, Li Y, Li B, Lok SWY, et al. Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria. Kidney Int. 2018;93:1367–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by statutory funds from the Medical University of Bialystok.

Author information

Affiliations

Authors

Contributions

IK, ZP: conceived and designed the experiments. ZP, ND, AL, MA: analyzed the data. ND, AL: contributed reagents/materials/analysis tools. ZP, ND: writing–original draft preparation. IK: writing – review and editing. IK, ZP, ND, MA, AL: approval of final manuscript.

Corresponding author

Correspondence to Irena Kasacka.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kasacka, I., Piotrowska, Z., Domian, N. et al. Canonical Wnt signaling in the kidney in different hypertension models. Hypertens Res 44, 1054–1066 (2021). https://doi.org/10.1038/s41440-021-00689-z

Download citation

Keywords

  • Wnt/β-catenin signaling
  • Kidney
  • Hypertension.

Search

Quick links