Calmodulin-dependent protein kinase II/cAMP response element-binding protein/Wnt/β-catenin signaling cascade regulates angiotensin II-induced podocyte injury and albuminuria.

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.

• Authors: Lei Jiang, Lingling Xu, Yuxian Song, Jianzhong Li, Junhua Mao, Allan Zijian Zhao, Weichun He, Junwei Yang, Chunsun Dai
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 32 Pg. 23368-79 (Aug 09 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23803607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CK59 compound
• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Dkk1 protein, mouse
• Intercellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• beta Catenin
• Angiotensin II
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Kinetin

Topics

• Albuminuria (genetics, metabolism, pathology)
• Angiotensin II (genetics, metabolism)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, metabolism)
• Cell Line, Transformed
• Cyclic AMP Response Element-Binding Protein (genetics, metabolism)
• Female
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Kinetin (pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Phosphorylation (drug effects, genetics)
• Podocytes (metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Wnt Signaling Pathway
• beta Catenin (genetics, metabolism)