Abstract
BackgroundAbnormal 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.MethodsWe 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.ResultsThe 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.ConclusionThese data suggest that the central WNT-RAS signaling plays a significant role in the development and progression of CKD.
Highlights
Wnt/β-catenin signaling plays an essential role in embryonic development, tissue homeostasis as well as organic injury and repairment [1,2,3]
Double-staining immunofluorescence showed that the marker gene green fluorescent protein (GFP) only expressed in ICV AAV-DKK1 group, and DKK1 concentration is dramatically up-regulated compared to the control (ICV vector) group in paraventricular nucleus (PVN) (Fig. 1)
The results showed that the key molecules of wnt/β-catenin signaling wnt3a and active-β-catenin significantly up-regulated in ICV vector+5/6NX group relative to sham group, but the up-regulation was inhibited in ICV DKK1+5/6NX group (Fig. 2)
Summary
Wnt/β-catenin signaling plays an essential role in embryonic development, tissue homeostasis as well as organic injury and repairment [1,2,3]. The abnormal regulation of RAS, including the intrarenal and cerebral RAS, is tightly associated with the onset and progression of renal injury [17]. It is reported that blocking cerebral RAS by intracerebroventricular injection (ICV) of losartan down-regulates intrarenal RAS expression in CKD rat model. 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. 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. 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.
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