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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.


Related in: MedlinePlus

PTC loss and α-SMA accumulation in response to a high salt diet.(a) Representative images of RECA-labeled PTCs in the renal cortexes of each group; white arrows indicate the loss of PTCs (magnification, 200X). (b–d) Split panel confocal immunofluorescence images of myofibroblasts (red) and mesenchymal cells (green) during the progression of SSHT in DS rats. Composite images of α-SMA and PDGFR-β are shown at the bottom of the panel. Note that most interstitial cells in DS rats fed a high salt diet co-expressed α-SMA and PDGFR-β (magnification, 400X). (e) Graph of the change in the PTC index in the DSH, DSN, and DSH-HCTZ groups at each time point. (f,g) Graphs of the α-SMA- and PDGFR-β-positive areas in the long-term experiment in the DSN, DSH, and DSH + HCTZ groups. *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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f4: PTC loss and α-SMA accumulation in response to a high salt diet.(a) Representative images of RECA-labeled PTCs in the renal cortexes of each group; white arrows indicate the loss of PTCs (magnification, 200X). (b–d) Split panel confocal immunofluorescence images of myofibroblasts (red) and mesenchymal cells (green) during the progression of SSHT in DS rats. Composite images of α-SMA and PDGFR-β are shown at the bottom of the panel. Note that most interstitial cells in DS rats fed a high salt diet co-expressed α-SMA and PDGFR-β (magnification, 400X). (e) Graph of the change in the PTC index in the DSH, DSN, and DSH-HCTZ groups at each time point. (f,g) Graphs of the α-SMA- and PDGFR-β-positive areas in the long-term experiment in the DSN, DSH, and DSH + HCTZ groups. *p < 0.05, **p < 0.01 versus DSN group. #p < 0.05, ##p < 0.01: DSH + HCTZ group versus DSH group.

Mentions: PTC maintenance appears to be critical for preventing progressive renal fibrosis, and the loss of PTCs was previously demonstrated to play an essential role in impairing blood flow in the etiology of interstitial fibrosis6. Using RECA-1 as an endothelium marker to evaluate PTC density, greater PTC loss was observed at week 6 in DSH rats compared with DSN rats, and these alterations worsened over time (Fig. 4a). Meanwhile, PTC loss was significantly prevented by HCTZ treatment (Fig. 4a); these results are expressed graphically in Fig. 4e.


Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis
PTC loss and α-SMA accumulation in response to a high salt diet.(a) Representative images of RECA-labeled PTCs in the renal cortexes of each group; white arrows indicate the loss of PTCs (magnification, 200X). (b–d) Split panel confocal immunofluorescence images of myofibroblasts (red) and mesenchymal cells (green) during the progression of SSHT in DS rats. Composite images of α-SMA and PDGFR-β are shown at the bottom of the panel. Note that most interstitial cells in DS rats fed a high salt diet co-expressed α-SMA and PDGFR-β (magnification, 400X). (e) Graph of the change in the PTC index in the DSH, DSN, and DSH-HCTZ groups at each time point. (f,g) Graphs of the α-SMA- and PDGFR-β-positive areas in the long-term experiment in the DSN, DSH, and DSH + HCTZ groups. *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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getmorefigures.php?uid=PMC5382679&req=5

f4: PTC loss and α-SMA accumulation in response to a high salt diet.(a) Representative images of RECA-labeled PTCs in the renal cortexes of each group; white arrows indicate the loss of PTCs (magnification, 200X). (b–d) Split panel confocal immunofluorescence images of myofibroblasts (red) and mesenchymal cells (green) during the progression of SSHT in DS rats. Composite images of α-SMA and PDGFR-β are shown at the bottom of the panel. Note that most interstitial cells in DS rats fed a high salt diet co-expressed α-SMA and PDGFR-β (magnification, 400X). (e) Graph of the change in the PTC index in the DSH, DSN, and DSH-HCTZ groups at each time point. (f,g) Graphs of the α-SMA- and PDGFR-β-positive areas in the long-term experiment in the DSN, DSH, and DSH + HCTZ groups. *p < 0.05, **p < 0.01 versus DSN group. #p < 0.05, ##p < 0.01: DSH + HCTZ group versus DSH group.
Mentions: PTC maintenance appears to be critical for preventing progressive renal fibrosis, and the loss of PTCs was previously demonstrated to play an essential role in impairing blood flow in the etiology of interstitial fibrosis6. Using RECA-1 as an endothelium marker to evaluate PTC density, greater PTC loss was observed at week 6 in DSH rats compared with DSN rats, and these alterations worsened over time (Fig. 4a). Meanwhile, PTC loss was significantly prevented by HCTZ treatment (Fig. 4a); these results are expressed graphically in Fig. 4e.

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