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Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis

View Article: PubMed Central - PubMed

ABSTRACT

Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH + HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/β-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/β-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension.

No MeSH data available.


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High salt diet induces apoptosis as well as renal tubule and interstitial cell proliferation in DS rats.Macrophage infiltration and inflammatory cytokine activation in DSH rats. (a) Representative images of TUNEL staining (brown staining) of the three groups at each time point. (magnification, 200X). (b) Immunostaining of Ki67 (green), which indicates renal cell proliferation, in each group (magnification, 200X). (c) Immunofluorescence images of CD68-labeled macrophages in each group at each time point (magnification, 200X). (d) Graph showing the number of TUNEL+ cells per HPF in the renal cortex in each group. (e,f) The chart depicting proliferating cells in the tubules and renal interstitium at each time point. (g) Morphometric quantification of the number of CD68+ cells (green) per HPF as an indicator of the degree of macrophage infiltration. (h–l) Quantitative RT-PCR was used to determine the mRNA levels of inflammatory cytokines and chemokines at the 12-week time point. Relative mRNA expression was determined after normalization to GAPDH, and the data are presented as the fold induction. *p < 0.05, **p < 0.01 versus DSN group. #p < 0.05, ##p < 0.01: DSH + HCTZ group versus DSH group.
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f5: High salt diet induces apoptosis as well as renal tubule and interstitial cell proliferation in DS rats.Macrophage infiltration and inflammatory cytokine activation in DSH rats. (a) Representative images of TUNEL staining (brown staining) of the three groups at each time point. (magnification, 200X). (b) Immunostaining of Ki67 (green), which indicates renal cell proliferation, in each group (magnification, 200X). (c) Immunofluorescence images of CD68-labeled macrophages in each group at each time point (magnification, 200X). (d) Graph showing the number of TUNEL+ cells per HPF in the renal cortex in each group. (e,f) The chart depicting proliferating cells in the tubules and renal interstitium at each time point. (g) Morphometric quantification of the number of CD68+ cells (green) per HPF as an indicator of the degree of macrophage infiltration. (h–l) Quantitative RT-PCR was used to determine the mRNA levels of inflammatory cytokines and chemokines at the 12-week time point. Relative mRNA expression was determined after normalization to GAPDH, and the data are presented as the fold induction. *p < 0.05, **p < 0.01 versus DSN group. #p < 0.05, ##p < 0.01: DSH + HCTZ group versus DSH group.

Mentions: Cell cycle arrest and cellular apoptosis are two of the major epithelial mechanisms that contribute to chronic tubulointerstitial fibrosis2324. Therefore, renal epithelial cell apoptosis and proliferation were assessed in the present study. The number of TUNEL-positive apoptotic cells significantly increased at week 6 in the DSH group. HCTZ administration markedly reduced the number of apoptotic cells (Fig. 5a and d). In addition, cell cycle labeling of kidney cells with the pan-cell cycle marker Ki67 showed that both interstitial cells and those of tubular origin were positive for Ki67 expression. As shown in Fig. 5b, proliferating cells were detected in the tubular epithelium and the interstitium. More Ki67+ cells were observed in the DSH group than in the DSN group (Fig. 5b and e). However, HCTZ treatment dramatically decreased the number of proliferating cells (Fig. 5b and e).


Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis
High salt diet induces apoptosis as well as renal tubule and interstitial cell proliferation in DS rats.Macrophage infiltration and inflammatory cytokine activation in DSH rats. (a) Representative images of TUNEL staining (brown staining) of the three groups at each time point. (magnification, 200X). (b) Immunostaining of Ki67 (green), which indicates renal cell proliferation, in each group (magnification, 200X). (c) Immunofluorescence images of CD68-labeled macrophages in each group at each time point (magnification, 200X). (d) Graph showing the number of TUNEL+ cells per HPF in the renal cortex in each group. (e,f) The chart depicting proliferating cells in the tubules and renal interstitium at each time point. (g) Morphometric quantification of the number of CD68+ cells (green) per HPF as an indicator of the degree of macrophage infiltration. (h–l) Quantitative RT-PCR was used to determine the mRNA levels of inflammatory cytokines and chemokines at the 12-week time point. Relative mRNA expression was determined after normalization to GAPDH, and the data are presented as the fold induction. *p < 0.05, **p < 0.01 versus DSN group. #p < 0.05, ##p < 0.01: DSH + HCTZ group versus DSH group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5382679&req=5

f5: High salt diet induces apoptosis as well as renal tubule and interstitial cell proliferation in DS rats.Macrophage infiltration and inflammatory cytokine activation in DSH rats. (a) Representative images of TUNEL staining (brown staining) of the three groups at each time point. (magnification, 200X). (b) Immunostaining of Ki67 (green), which indicates renal cell proliferation, in each group (magnification, 200X). (c) Immunofluorescence images of CD68-labeled macrophages in each group at each time point (magnification, 200X). (d) Graph showing the number of TUNEL+ cells per HPF in the renal cortex in each group. (e,f) The chart depicting proliferating cells in the tubules and renal interstitium at each time point. (g) Morphometric quantification of the number of CD68+ cells (green) per HPF as an indicator of the degree of macrophage infiltration. (h–l) Quantitative RT-PCR was used to determine the mRNA levels of inflammatory cytokines and chemokines at the 12-week time point. Relative mRNA expression was determined after normalization to GAPDH, and the data are presented as the fold induction. *p < 0.05, **p < 0.01 versus DSN group. #p < 0.05, ##p < 0.01: DSH + HCTZ group versus DSH group.
Mentions: Cell cycle arrest and cellular apoptosis are two of the major epithelial mechanisms that contribute to chronic tubulointerstitial fibrosis2324. Therefore, renal epithelial cell apoptosis and proliferation were assessed in the present study. The number of TUNEL-positive apoptotic cells significantly increased at week 6 in the DSH group. HCTZ administration markedly reduced the number of apoptotic cells (Fig. 5a and d). In addition, cell cycle labeling of kidney cells with the pan-cell cycle marker Ki67 showed that both interstitial cells and those of tubular origin were positive for Ki67 expression. As shown in Fig. 5b, proliferating cells were detected in the tubular epithelium and the interstitium. More Ki67+ cells were observed in the DSH group than in the DSN group (Fig. 5b and e). However, HCTZ treatment dramatically decreased the number of proliferating cells (Fig. 5b and e).

View Article: PubMed Central - PubMed

ABSTRACT

Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH&thinsp;+&thinsp;HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/&beta;-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/&beta;-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension.

No MeSH data available.


Related in: MedlinePlus