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Effect of berberine on the renal tubular epithelial-to-mesenchymal transition by inhibition of the Notch/snail pathway in diabetic nephropathy model KKAy mice

View Article: PubMed Central - PubMed

ABSTRACT

Renal tubular epithelial-to-mesenchymal transition (EMT) and renal tubular interstitial fibrosis are the main pathological changes of diabetic nephropathy (DN), which is a common cause of end-stage renal disease. Previous studies have suggested that berberine (BBR) has antifibrotic effects in the kidney and can reduce apoptosis and inhibit the EMT of podocytes in DN. However, the effect of BBR on the renal tubular EMT in DN and its mechanisms of action are unknown. This study was performed to explore the effects of BBR on the renal tubular EMT and the molecular mechanisms of BBR in DN model KKAy mice and on the high glucose (HG)-induced EMT in mouse renal tubular epithelial cells. Our results showed that, relative to the model mice, the mice in the treatment group had an improved general state and reduced blood glucose and 24-h urinary protein levels. Degradation of renal function was ameliorated by BBR. We also observed the protective effects of BBR on renal structural changes, including normalization of an index of renal interstitial fibrosis and kidney weight/body weight. Moreover, BBR suppressed the activation of the Notch/snail pathway and upregulated the α-SMA and E-cadherin levels in DN model KKAy mice. BBR was further found to prevent HG-induced EMT events and to inhibit the HG-induced expression of Notch pathway members and snail1 in mouse renal tubular epithelial cells. Our findings indicate that BBR has a therapeutic effect on DN, including its inhibition of the renal tubular EMT and renal interstitial fibrosis. Furthermore, the BBR-mediated EMT inhibition occurs through Notch/snail pathway regulation.

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Berberine inhibits activation of the Notch pathway in DN model KKAy mice.Notes: (A) Representative photographs of immunohistochemistry for Jagged1, Notch1, and Hes1 in DN model KKAy mice, 400×. (B) Representative band of Jagged1, Notch1, and Hes1 proteins by Western blot in DN model KKAy mice. (C) Representative photographs of in situ hybridization for Jagged1, notch1, and Hes1 in DN model KKAy mice, 400×. (D) Comparison of MOD of Jagged1, notch1, and Hes1 proteins in DN model KKAy mice. (E) Comparison of the gray value of Jagged1, Notch1, and Hes1 proteins in DN model KKAy mice (n=3). **P<0.01 and ##P<0.01, #P<0.05 compared with the MG.Abbreviations: DN, diabetic nephropathy; MG, model group; MOD, mean optical density; NG, normal control group; TG, treatment group.
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f6-dddt-11-1065: Berberine inhibits activation of the Notch pathway in DN model KKAy mice.Notes: (A) Representative photographs of immunohistochemistry for Jagged1, Notch1, and Hes1 in DN model KKAy mice, 400×. (B) Representative band of Jagged1, Notch1, and Hes1 proteins by Western blot in DN model KKAy mice. (C) Representative photographs of in situ hybridization for Jagged1, notch1, and Hes1 in DN model KKAy mice, 400×. (D) Comparison of MOD of Jagged1, notch1, and Hes1 proteins in DN model KKAy mice. (E) Comparison of the gray value of Jagged1, Notch1, and Hes1 proteins in DN model KKAy mice (n=3). **P<0.01 and ##P<0.01, #P<0.05 compared with the MG.Abbreviations: DN, diabetic nephropathy; MG, model group; MOD, mean optical density; NG, normal control group; TG, treatment group.

Mentions: The Notch pathway induces conformational changes of the Notch receptor (Notch1) by ligand (jagged1) and receptor binding, and the activated form of Notch (Notch intracellular domain) is released under the guidance of γ-secretase, which activates the downstream genes hes and hey after entry into the nucleus, regulating cell transdifferentiation and inducing cell differentiation.32 In our study, jagged1, notch1, and hes1 expression levels were detected by Western blot and immunohistochemistry (Figure 6A and B), while their mRNA levels were detected by ISH (Figure 6C). Our results show that the jagged1, notch1, and hes1 protein and mRNA levels were increased, suggesting that the Notch pathway was activated in the MG relative to the NG (P<0.01; Figure 6D–F). After 16 weeks of treatment, BBR decreased the protein and mRNA levels of jagged1, notch1, and hes1 in the DN model KKAy mice (P<0.01; Figure 6D–F), indicating that Notch pathway activation was blocked in DN model KKAy mice.


Effect of berberine on the renal tubular epithelial-to-mesenchymal transition by inhibition of the Notch/snail pathway in diabetic nephropathy model KKAy mice
Berberine inhibits activation of the Notch pathway in DN model KKAy mice.Notes: (A) Representative photographs of immunohistochemistry for Jagged1, Notch1, and Hes1 in DN model KKAy mice, 400×. (B) Representative band of Jagged1, Notch1, and Hes1 proteins by Western blot in DN model KKAy mice. (C) Representative photographs of in situ hybridization for Jagged1, notch1, and Hes1 in DN model KKAy mice, 400×. (D) Comparison of MOD of Jagged1, notch1, and Hes1 proteins in DN model KKAy mice. (E) Comparison of the gray value of Jagged1, Notch1, and Hes1 proteins in DN model KKAy mice (n=3). **P<0.01 and ##P<0.01, #P<0.05 compared with the MG.Abbreviations: DN, diabetic nephropathy; MG, model group; MOD, mean optical density; NG, normal control group; TG, treatment group.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5384688&req=5

f6-dddt-11-1065: Berberine inhibits activation of the Notch pathway in DN model KKAy mice.Notes: (A) Representative photographs of immunohistochemistry for Jagged1, Notch1, and Hes1 in DN model KKAy mice, 400×. (B) Representative band of Jagged1, Notch1, and Hes1 proteins by Western blot in DN model KKAy mice. (C) Representative photographs of in situ hybridization for Jagged1, notch1, and Hes1 in DN model KKAy mice, 400×. (D) Comparison of MOD of Jagged1, notch1, and Hes1 proteins in DN model KKAy mice. (E) Comparison of the gray value of Jagged1, Notch1, and Hes1 proteins in DN model KKAy mice (n=3). **P<0.01 and ##P<0.01, #P<0.05 compared with the MG.Abbreviations: DN, diabetic nephropathy; MG, model group; MOD, mean optical density; NG, normal control group; TG, treatment group.
Mentions: The Notch pathway induces conformational changes of the Notch receptor (Notch1) by ligand (jagged1) and receptor binding, and the activated form of Notch (Notch intracellular domain) is released under the guidance of γ-secretase, which activates the downstream genes hes and hey after entry into the nucleus, regulating cell transdifferentiation and inducing cell differentiation.32 In our study, jagged1, notch1, and hes1 expression levels were detected by Western blot and immunohistochemistry (Figure 6A and B), while their mRNA levels were detected by ISH (Figure 6C). Our results show that the jagged1, notch1, and hes1 protein and mRNA levels were increased, suggesting that the Notch pathway was activated in the MG relative to the NG (P<0.01; Figure 6D–F). After 16 weeks of treatment, BBR decreased the protein and mRNA levels of jagged1, notch1, and hes1 in the DN model KKAy mice (P<0.01; Figure 6D–F), indicating that Notch pathway activation was blocked in DN model KKAy mice.

View Article: PubMed Central - PubMed

ABSTRACT

Renal tubular epithelial-to-mesenchymal transition (EMT) and renal tubular interstitial fibrosis are the main pathological changes of diabetic nephropathy (DN), which is a common cause of end-stage renal disease. Previous studies have suggested that berberine (BBR) has antifibrotic effects in the kidney and can reduce apoptosis and inhibit the EMT of podocytes in DN. However, the effect of BBR on the renal tubular EMT in DN and its mechanisms of action are unknown. This study was performed to explore the effects of BBR on the renal tubular EMT and the molecular mechanisms of BBR in DN model KKAy mice and on the high glucose (HG)-induced EMT in mouse renal tubular epithelial cells. Our results showed that, relative to the model mice, the mice in the treatment group had an improved general state and reduced blood glucose and 24-h urinary protein levels. Degradation of renal function was ameliorated by BBR. We also observed the protective effects of BBR on renal structural changes, including normalization of an index of renal interstitial fibrosis and kidney weight/body weight. Moreover, BBR suppressed the activation of the Notch/snail pathway and upregulated the &alpha;-SMA and E-cadherin levels in DN model KKAy mice. BBR was further found to prevent HG-induced EMT events and to inhibit the HG-induced expression of Notch pathway members and snail1 in mouse renal tubular epithelial cells. Our findings indicate that BBR has a therapeutic effect on DN, including its inhibition of the renal tubular EMT and renal interstitial fibrosis. Furthermore, the BBR-mediated EMT inhibition occurs through Notch/snail pathway regulation.

No MeSH data available.


Related in: MedlinePlus