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

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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.

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High salt loading induces glomerular injury with progressive glomerulosclerosis in DS rats.(a) Representative immunofluorescence images of glomerular synaptopodin staining in DS rats (magnification, 400X). (b) Representative immunofluorescence images of glomerular desmin staining in DS rats (magnification, 400X). (c) Representative light microscopy images (PASM) of glomeruli from 12 weeks; the DSH group exhibited serious glomerulosclerosis (arrowheads) compared with the DSN group, and HCTZ treatment decreased the appearance of glomerulosclerosis (magnification, 100X). (d) Transmission electron micrographs of glomeruli. Scale bar, 2 μm. (e,f) Chart of the quantification of the fluorescence staining intensity of glomerular synaptopodin and desmin. (g) Quantification of glomerulosclerosis at each time point. *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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f3: High salt loading induces glomerular injury with progressive glomerulosclerosis in DS rats.(a) Representative immunofluorescence images of glomerular synaptopodin staining in DS rats (magnification, 400X). (b) Representative immunofluorescence images of glomerular desmin staining in DS rats (magnification, 400X). (c) Representative light microscopy images (PASM) of glomeruli from 12 weeks; the DSH group exhibited serious glomerulosclerosis (arrowheads) compared with the DSN group, and HCTZ treatment decreased the appearance of glomerulosclerosis (magnification, 100X). (d) Transmission electron micrographs of glomeruli. Scale bar, 2 μm. (e,f) Chart of the quantification of the fluorescence staining intensity of glomerular synaptopodin and desmin. (g) Quantification of glomerulosclerosis at each time point. *p < 0.05, **p < 0.01 versus DSN group. #p < 0.05, ##p < 0.01: DSH + HCTZ group versus DSH group.

Mentions: DSH rats showed marked proteinuria (Fig. 1d), which could be associated with podocyte injury. We evaluated podocytes based on synaptopodin (a typical normal podocyte marker) and desmin (a conventional podocyte injury marker) expression by immunofluorescence2122. Markedly decreased synaptopodin expression was observed in the DSH group compared with the DSN group (Fig. 3a), but treatment with HCTZ significantly reversed this change (Fig. 3a). The results are expressed graphically in Fig. 3e. Significantly enhanced desmin expression was observed in the DSH group compared with the DSN group (Fig. 3b), but HCTZ treatment markedly attenuated this alteration (Fig. 3b); these results are expressed graphically in Fig. 3f. Additionally, more severe focal-segmental or global glomerulosclerosis occurred in the DSH group compared with the DSN group (Fig. 3c); HCTZ treatment significantly reduced the glomerular damage in DSH rats (Fig. 3c), and these results are expressed graphically in Fig. 3g. We further assessed podocyte damage by transmission electron microscopy (Fig. 3d). The podocytes of DSH rats showed a lack of slit diaphragms and the appearance of foot process effacement and fusion at 12 weeks (Fig. 3d). On the other hand, HCTZ restored the podocyte injury towards normal in the glomerular of DSH group (Fig. 3d). These findings indicate that SSHT-induced podocyte dysfunction might be involved in the development of glomerulosclerosis, leading to tubulointerstitial fibrosis.


Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis
High salt loading induces glomerular injury with progressive glomerulosclerosis in DS rats.(a) Representative immunofluorescence images of glomerular synaptopodin staining in DS rats (magnification, 400X). (b) Representative immunofluorescence images of glomerular desmin staining in DS rats (magnification, 400X). (c) Representative light microscopy images (PASM) of glomeruli from 12 weeks; the DSH group exhibited serious glomerulosclerosis (arrowheads) compared with the DSN group, and HCTZ treatment decreased the appearance of glomerulosclerosis (magnification, 100X). (d) Transmission electron micrographs of glomeruli. Scale bar, 2 μm. (e,f) Chart of the quantification of the fluorescence staining intensity of glomerular synaptopodin and desmin. (g) Quantification of glomerulosclerosis at each time point. *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

f3: High salt loading induces glomerular injury with progressive glomerulosclerosis in DS rats.(a) Representative immunofluorescence images of glomerular synaptopodin staining in DS rats (magnification, 400X). (b) Representative immunofluorescence images of glomerular desmin staining in DS rats (magnification, 400X). (c) Representative light microscopy images (PASM) of glomeruli from 12 weeks; the DSH group exhibited serious glomerulosclerosis (arrowheads) compared with the DSN group, and HCTZ treatment decreased the appearance of glomerulosclerosis (magnification, 100X). (d) Transmission electron micrographs of glomeruli. Scale bar, 2 μm. (e,f) Chart of the quantification of the fluorescence staining intensity of glomerular synaptopodin and desmin. (g) Quantification of glomerulosclerosis at each time point. *p < 0.05, **p < 0.01 versus DSN group. #p < 0.05, ##p < 0.01: DSH + HCTZ group versus DSH group.
Mentions: DSH rats showed marked proteinuria (Fig. 1d), which could be associated with podocyte injury. We evaluated podocytes based on synaptopodin (a typical normal podocyte marker) and desmin (a conventional podocyte injury marker) expression by immunofluorescence2122. Markedly decreased synaptopodin expression was observed in the DSH group compared with the DSN group (Fig. 3a), but treatment with HCTZ significantly reversed this change (Fig. 3a). The results are expressed graphically in Fig. 3e. Significantly enhanced desmin expression was observed in the DSH group compared with the DSN group (Fig. 3b), but HCTZ treatment markedly attenuated this alteration (Fig. 3b); these results are expressed graphically in Fig. 3f. Additionally, more severe focal-segmental or global glomerulosclerosis occurred in the DSH group compared with the DSN group (Fig. 3c); HCTZ treatment significantly reduced the glomerular damage in DSH rats (Fig. 3c), and these results are expressed graphically in Fig. 3g. We further assessed podocyte damage by transmission electron microscopy (Fig. 3d). The podocytes of DSH rats showed a lack of slit diaphragms and the appearance of foot process effacement and fusion at 12 weeks (Fig. 3d). On the other hand, HCTZ restored the podocyte injury towards normal in the glomerular of DSH group (Fig. 3d). These findings indicate that SSHT-induced podocyte dysfunction might be involved in the development of glomerulosclerosis, leading to tubulointerstitial 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&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