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.