The regulation effect of WNT-RAS signaling in hypothalamic paraventricular nucleus on renal fibrosis

BACKGROUND: Abnormal activation of wnt/β-catenin signaling and renin-angiotensin system is known to play a vital role in the development and progression of CKD. We hypothesized that abnormal expression of central wnt/β-catenin signaling and renin-angiotensin system (WNT-RAS signaling) was tightly involved in CKD. METHODS: We established sham-operated and 5/6 nephrectomized (5/6 NX) rat model and blocked the central wnt signaling by intracerebroventricular injection of adeno-associated virus vector which can overexpress target gene DKK1. The central and renal expression level of wnt/β-catenin signaling and RAS and renal injury were assessed. RESULTS: The expression levels of the main wnt/β-catenin signaling components in both brain and kidney of 5/6NX rats, such as wnt3a and active-β-catenin, were elevated obviously and the up-regulation were inhibited by central blockade of the wnt signaling. Furthermore, the expression of the major components of RAS in both brain and kidney in 5/6NX rats, such as angiotensinogen (AGT), angiotensin converting enzyme (ACE-1), angiotensin II AT1-receptor (AT1R), was significantly up-regulated and the up-regulated expression was inhibited by central blockade of the wnt singling. Notably, central blockade of the wnt signaling improved renal function as indicated by decreased serum creatinine and 24 h urinary protein, and attenuated interstitial fibrosis as indicated by reduced Sirius red staining and expression of Fibronectin, Collagen-I and α-SMA. CONCLUSION: These data suggest that the central WNT-RAS signaling plays a significant role in the development and progression of CKD.