Abstract
Angiotensin II (Ang II) plays a pivotal role in promoting podocyte dysfunction and albuminuria, however, the underlying mechanisms have not been fully delineated. In this study, we found that Ang II induced Wnt1 expression and β-catenin nuclear translocation in cultured mouse podocytes. Blocking Wnt signaling with Dickkopf-1 (Dkk1) or β-catenin siRNA attenuated Ang II-induced podocyte injury. Ang II could also induce the phosphorylation of calmodulin-dependent protein kinase (CaMK) II and cAMP response element-binding protein (CREB) in cultured podocytes. Blockade of this pathway with CK59 or CREB siRNA could significantly inhibit Ang II-induced Wnt/β-catenin signaling and podocyte injury. In in vivo studies, administration of Ang II promoted Wnt/β-catenin signaling, aggregated podocyte damage, and albuminuria in mice. CK59 could remarkably ameliorate Ang II-induced podocyte injury and albuminuria. Furthermore, ectopic expression of exogenous Dkk1 also attenuated Ang II-induced podocytopathy in mice. Taken together, this study demonstrates that the CaMK II/CREB/Wnt/β-catenin signaling cascade plays an important role in regulating Ang II-induced podocytopathy. Targeting this signaling pathway may offer renal protection against the development of proteinuric kidney diseases.
Highlights
The mechanisms for angiotensin (Ang) II-induced podocytopathy are not clear
This study demonstrates that the calmodulin-dependent protein kinase (CaMK) II/cAMP response element-binding protein (CREB)/Wnt/-catenin signaling cascade plays an important role in regulating Angiotensin II (Ang II)-induced podocytopathy
This study provides a mechanistic insight about CaMK II/CREB/Wnt/-catenin signaling in Ang II-induced podocyte damage and albuminuria
Summary
Results: Ang II induced calmodulin-dependent protein kinase (CaMK) II/cAMP response element-binding protein (CREB) and Wnt/-catenin signaling activation in podocytes. Ang II could induce the phosphorylation of calmodulin-dependent protein kinase (CaMK) II and cAMP response element-binding protein (CREB) in cultured podocytes. Blockade of this pathway with CK59 or CREB siRNA could significantly inhibit Ang II-induced Wnt/-catenin signaling and podocyte injury. This study demonstrates that the CaMK II/CREB/Wnt/-catenin signaling cascade plays an important role in regulating Ang II-induced podocytopathy. Targeting this signaling pathway may offer renal protection against the development of proteinuric kidney diseases
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