casein-kinase-ii and Nephritis--Interstitial

TGFβ1/Smad, Wnt/β-catenin and snail1 are preferentially activated in renal tubular epithelia after injury, leading to epithelial-mesenchymal transition (EMT). The stress response is coupled to EMT and kidney injury; however, the underlying mechanism of the stress response in EMT remains elusive. AMP-activated protein kinase (AMPK) signalling is responsive to stress and regulates cell energy balance and differentiation. We found that knockdown of AMPKα, especially AMPKα2, enhanced EMT by up-regulating β-catenin and Smad3 in vitro. AMPKα2 deficiency enhanced EMT and fibrosis in a murine unilateral ureteral obstruction (UUO) model. AMPKα2 deficiency also increased the expression of chemokines KC and MCP-1, along with enhanced infiltration of inflammatory cells into the kidney after UUO. CK2β interacted physically with AMPKα and enhanced AMPKα Thr172 phosphorylation and its catalytic activity. Thus, activated AMPKα signalling suppresses EMT and secretion of chemokines in renal tubular epithelia through interaction with CK2β to attenuate renal injury.

Topics: AMP-Activated Protein Kinases; Animals; beta Catenin; Casein Kinase II; Cell Line; Cell Transdifferentiation; Chemokine CCL2; Chemokine CXCL1; Disease Models, Animal; Enzyme Activation; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Inflammation Mediators; Kidney Tubules, Proximal; Mice, Inbred C57BL; Mice, Knockout; Nephritis, Interstitial; Protein Binding; RNA Interference; Smad3 Protein; Transfection; Ureteral Obstruction; Wnt Signaling Pathway

The high-energy requirement of the kidney and the importance of energy metabolism in renal physiology has been appreciated for decades, but only recently has there emerged a strong link between impaired renal energy metabolism and chronic kidney disease (CKD). The mechanisms underlying the association between changes in energy metabolism and progression of CKD, however, remain poorly understood. A new study from Qiu and colleagues reported in the Journal of Pathology has advanced this understanding by showing that, after renal injury, the energy sensor AMPK inhibits epithelial-mesenchymal transition and inflammation, processes important in the pathogenesis of CKD. Furthermore, this study identifies an interaction between AMPK and CK2β as an important mechanism in the anti-fibrotic effect. CK2β has previously been shown to interact with STK11 (also known as LKB1) to regulate cellular polarity. These findings are consistent with the known roles of the LKB1-AMPK pathway in sustaining cellular energy homeostasis and epithelial cell polarity, and add to growing evidence linking the suppression of energy metabolism to CKD. They emphasize the importance of energy metabolism in general and the LKB1-AMPK axis in particular as key investigational and therapeutic targets in the battle against CKD.

Topics: AMP-Activated Protein Kinases; Animals; Casein Kinase II; Cell Transdifferentiation; Epithelial Cells; Epithelial-Mesenchymal Transition; Humans; Kidney Tubules, Proximal; Nephritis, Interstitial