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Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/β‑catenin pathway independent of DKK1

  • Authors:
    • Xiaohui Wang
    • Xiaoxia Chang
    • Donglin Yang
    • Lixia Zhang
    • Zijie Guo
    • Xuhong Sun
    • Aiqun Li
    • Yanbo Ni
    • Pengchao Du
  • View Affiliations / Copyright

    Affiliations: Department of Endocrinology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China, Department of Cardiology, Muping Hospital of Traditional Chinese Medicine, Yantai, Shandong 264100, P.R. China, School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong 264003, P.R. China, Emergency Department, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 208
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    Published online on: August 27, 2025
       https://doi.org/10.3892/etm.2025.12958
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Abstract

Acute kidney injury (AKI) is a group of common clinical syndromes characterized by a rapid decline in renal function over a short period of time. At present, the treatment methods are limited, and research is needed to identify drugs that could alleviate renal ischemia‑reperfusion (I/R) injury. Tetramethylpyrazine (TMP) is a bioactive alkaloid extracted from the Chinese herbal medicine Chuanxiong. TMP is known to possess various anti‑inflammatory and cardiovascular and renal protective effects; however, the therapeutic molecular targets are still unclear. In the present study, using a rat renal I/R model, the effects of TMP on renal injury, dickkopf‑1 (DKK1) expression, Wnt/β‑catenin signaling and apoptosis were evaluated through morphological examination, renal function tests, western blotting, immunohistochemistry and TUNEL assays. It was determined that TMP ameliorated tubular pathologic injury and improved renal function in rats following renal I/R. In addition, in rats following I/R, TMP promoted the expression of DKK1, an inhibitor of the Wnt/β‑catenin signaling pathway, in renal tissues, activated the Wnt/β‑catenin signaling pathway in kidney tissues and reduced apoptosis of renal cells. To the best of our knowledge, the present study is the first to investigate the regulatory effects of TMP on DKK1 and the Wnt/β‑catenin signaling pathway, revealing that TMP could attenuate AKI by activating Wnt/β‑catenin signaling independent of the inhibitory effect of DKK1.
View Figures

Figure 1

TMP protects against acute kidney
injury by alleviating renal tubular pathological injury and
improving renal function following I/R in a rat model. (A) Serum
creatinine and (B) blood urea nitrogen levels of rats in different
groups were measured using a biochemical analyzer. n=6. (C) Body
weight in different groups. n=6. (D) Representative H&E images
showing the renal morphological changes (black arrows) and renal
tubular damage scores of rats in different groups. Scale bars, 20
µm, magnification, x400. n=10. *P<0.05,
**P<0.01, ***P<0.001,
****P<0.0001. I/R, ischemia-reperfusion; TMP,
tetramethylpyrazine; H&E hematoxylin and eosin.

Figure 2

TMP promotes the expression of DKK1
in the renal tissue of rats following I/R. (A) Representative
western blots and semi-quantified data showing the expression of
DKK1 in the renal tissue of rats in the sham, I/R and I/R + TMP
groups. n=6. (B) Representative IHC images of DKK1 in the renal
tissue of rats in the sham, I/R and I/R + TMP groups, and
semi-quantification. n=3. IHC images: Top row, scale bars, 200 µm,
magnification, x40; bottom row, scale bars, 20 µm, magnification,
x400. *P<0.05, **P<0.01,
***P<0.001, ****P<0.0001. I/R,
ischemia-reperfusion; TMP, tetramethylpyrazine; DKK1, dickkopf-1;
IHC, immunohistochemistry.

Figure 3

TMP activates the Wnt/β-catenin
signaling pathway in the kidney of rats following I/R. (A)
Representative western blots and semi-quantified protein levels
showing the expression levels of Wnt1 in the renal tissue of rats
in different groups. n=6. (B) Representative IHC images and protein
semi-quantification of Wnt1 in the renal tissue of rats in the
sham, I/R and I/R + TMP groups. n=3. (C) Representative western
blots and semi-quantified protein levels showing the expression
levels of β-catenin in the renal tissue of rats in different
groups. n=6. (D) Representative IHC images and protein
semi-quantification of β-catenin in the renal tissue of rats in the
sham, I/R and I/R + TMP groups. n=3. IHC images: Top row, scale
bars, 200 µm, magnification, x40; bottom row, scale bars, 20 µm,
magnification, x400. *P<0.05, **P<0.01,
****P<0.0001. I/R, ischemia-reperfusion; TMP,
tetramethylpyrazine; IHC, immunohistochemistry.

Figure 4

TMP ameliorates renal cell apoptosis
after I/R in rats. (A) TUNEL staining showing the renal cell
apoptosis levels in different groups. Scale bars, 50 µm. n=3.
Representative IHC images and protein semi-quantification of (B)
Bax and (C) caspase-3 in renal tissue of rats in different groups.
n=3. (D) Relative ratio of cleaved caspase-3/caspase-3 determined
by western blotting. n=6. (E) Representative images and protein
semi-quantification of Bcl-2 in the renal tissue of rats in
different groups. n=3. (F) Representative western blots and
semi-quantified protein levels showing the expression levels of
Bcl-2 in the renal tissue of rats in different groups. n=6. IHC
images: Top row, scale bars, 200 µm, magnification, x40; bottom
row, scale bars, 20 µm, magnification, x400. *P<0.05,
**P<0.01, ***P<0.001. I/R,
ischemia-reperfusion; TMP, tetramethylpyrazine; IHC,
immunohistochemistry.
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Copy and paste a formatted citation
Spandidos Publications style
Wang X, Chang X, Yang D, Zhang L, Guo Z, Sun X, Li A, Ni Y and Du P: Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/&beta;‑catenin pathway independent of DKK1. Exp Ther Med 30: 208, 2025.
APA
Wang, X., Chang, X., Yang, D., Zhang, L., Guo, Z., Sun, X. ... Du, P. (2025). Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/&beta;‑catenin pathway independent of DKK1. Experimental and Therapeutic Medicine, 30, 208. https://doi.org/10.3892/etm.2025.12958
MLA
Wang, X., Chang, X., Yang, D., Zhang, L., Guo, Z., Sun, X., Li, A., Ni, Y., Du, P."Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/&beta;‑catenin pathway independent of DKK1". Experimental and Therapeutic Medicine 30.5 (2025): 208.
Chicago
Wang, X., Chang, X., Yang, D., Zhang, L., Guo, Z., Sun, X., Li, A., Ni, Y., Du, P."Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/&beta;‑catenin pathway independent of DKK1". Experimental and Therapeutic Medicine 30, no. 5 (2025): 208. https://doi.org/10.3892/etm.2025.12958
Copy and paste a formatted citation
x
Spandidos Publications style
Wang X, Chang X, Yang D, Zhang L, Guo Z, Sun X, Li A, Ni Y and Du P: Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/&beta;‑catenin pathway independent of DKK1. Exp Ther Med 30: 208, 2025.
APA
Wang, X., Chang, X., Yang, D., Zhang, L., Guo, Z., Sun, X. ... Du, P. (2025). Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/&beta;‑catenin pathway independent of DKK1. Experimental and Therapeutic Medicine, 30, 208. https://doi.org/10.3892/etm.2025.12958
MLA
Wang, X., Chang, X., Yang, D., Zhang, L., Guo, Z., Sun, X., Li, A., Ni, Y., Du, P."Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/&beta;‑catenin pathway independent of DKK1". Experimental and Therapeutic Medicine 30.5 (2025): 208.
Chicago
Wang, X., Chang, X., Yang, D., Zhang, L., Guo, Z., Sun, X., Li, A., Ni, Y., Du, P."Tetramethylpyrazine alleviates acute kidney injury by activating the Wnt/&beta;‑catenin pathway independent of DKK1". Experimental and Therapeutic Medicine 30, no. 5 (2025): 208. https://doi.org/10.3892/etm.2025.12958
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