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.
Highlights
Dahl saltsensitive (DS) rats that consume a high salt diet develop sensitive hypertension (SSHT) and chronic ischemic nephropathy, which has been demonstrated to induce renal inflammation, tubular atrophy, and interstitial fibrosis, eventually leading to renal dysfunction[3]
This study revealed that after the administration of an 8% high salt diet, DS rats developed aggravated renal interstitial fibrosis, tubular epithelial injury and glomerular damage over time
DS rats fed a high salt diet resulted in obvious peritubular capillary (PTC) loss, macrophage infiltration, apoptosis and cell proliferation following increased blood pressure
Summary
DS rats that consume a high salt diet develop SSHT and chronic ischemic nephropathy, which has been demonstrated to induce renal inflammation, tubular atrophy, and interstitial fibrosis, eventually leading to renal dysfunction[3]. Macrophages play important roles in health and disease, with functions including immune surveillance, bacterial killing, tissue remodeling and repair, and the clearance of cell debris[10]. Our previous studies provided evidence that macrophages play an active role in regeneration and repair through canonical Wnt/β-catenin signaling during kidney injury. Appears to be silenced and reactivated in diverse adult kidney diseases, including ischemia/reperfusion injury, glomerular diseases, diabetic nephropathy, obstructive nephropathy, and polycystic kidney disease[17,18] Consistent with these observations, changes in Wnt ligands are associated with activation of the Wnt/β-catenin pathway. We investigated whether Wnt/β-catenin signaling and the activation of Wnt ligands are associated with the development of SSHT-induced chronic kidney disease
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