Abstract
A number of signal transduction pathways are activated during Acute Kidney Injury (AKI). Of particular interest is the Salt Inducible Kinase (SIK) signaling network, and its effects on the Renal Proximal Tubule (RPT), one of the primary targets of injury in AKI. The SIK1 network is activated in the RPT following an increase in intracellular Na+ (Na+in), resulting in an increase in Na,K-ATPase activity, in addition to the phosphorylation of Class IIa Histone Deacetylases (HDACs). In addition, activated SIKs repress transcriptional regulation mediated by the interaction between cAMP Regulatory Element Binding Protein (CREB) and CREB Regulated Transcriptional Coactivators (CRTCs). Through their transcriptional effects, members of the SIK family regulate a number of metabolic processes, including such cellular processes regulated during AKI as fatty acid metabolism and mitochondrial biogenesis. SIKs are involved in regulating a number of other cellular events which occur during AKI, including apoptosis, the Epithelial to Mesenchymal Transition (EMT), and cell division. Recently, the different SIK kinase isoforms have emerged as promising drug targets, more than 20 new SIK2 inhibitors and activators having been identified by MALDI-TOF screening assays. Their implementation in the future should prove to be important in such renal disease states as AKI.
Highlights
Salt Inducible Kinase (SIK) was first discovered in the adrenal gland of rats on a high salt diet, where it plays a regulatory role in steroidogenesis [1]
The necessary increases in intracellular cAMP and Ca2+in required for the interaction of CREB Regulated Transcriptional Coactivators (CRTCs) with cAMP Regulatory Element Binding Protein (CREB) on the atp1b1 promoter must occur if Renal Proximal Tubule (RPT) transport activity is to increase over the long term
Reactive Oxygen Species (ROS) are generated due to injuries affecting the mitochondria. These problems can be alleviated by means of mitochondrial biogenesis, which depends upon the expression of the Peroxisome Proliferator-Activated Receptor γ Co-activator-1α (PGC-1α) gene, which in turn depends upon SIKs
Summary
Salt Inducible Kinase (SIK) was first discovered in the adrenal gland of rats on a high salt diet, where it plays a regulatory role in steroidogenesis [1]. A SIK network was identified that plays an important role in regulating Na+ reabsorption in the Renal Proximal Tubule (RPT) [2]. Following the initiation and extension phases caused by the insults, the kidney goes through maintenance and recovery phases, during which repair occurs in cells that are sub-lethally damaged, in addition to the generation of new cells. There is a need to understand the underlying molecular changes that occur in the tubule epithelial cells during AKI, and the recovery period, so as to develop effective therapies. There is considerable evidence suggesting that signal transduction pathways that are activated during AKI involve different aspects of the SIK Networks, which opens up the possibility of new avenues for therapy. 2. Role of the Salt Inducible Kinase 1 (SIK1) Network in the Response of the Renal Proximal Tubule (RPT) to Injury
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