Gene Level Regulation of Na,K-ATPase in the Renal Proximal Tubule Is Controlled by Two Independent but Interacting Regulatory Mechanisms Involving Salt Inducible Kinase 1 and CREB-Regulated Transcriptional Coactivators

Abstract

For many years, studies concerning the regulation of Na,K-ATPase were restricted to acute regulatory mechanisms, which affected the phosphorylation of Na,K-ATPase, and thus its retention on the plasma membrane. However, in recent years, this focus has changed. Na,K-ATPase has been established as a signal transducer, which becomes part of a signaling complex as a consequence of ouabain binding. Na,K-ATPase within this signaling complex is localized in caveolae, where Na,K-ATPase has also been observed to regulate Inositol 1,4,5-Trisphosphate Receptor (IP3R)-mediated calcium release. This latter association has been implicated as playing a role in signaling by G Protein Coupled Receptors (GPCRs). Here, the consequences of signaling by renal effectors that act via such GPCRs are reviewed, including their regulatory effects on Na,K-ATPase gene expression in the renal proximal tubule (RPT). Two major types of gene regulation entail signaling by Salt Inducible Kinase 1 (SIK1). On one hand, SIK1 acts so as to block signaling via cAMP Response Element (CRE) Binding Protein (CREB) Regulated Transcriptional Coactivators (CRTCs) and on the other hand, SIK1 acts so as to stimulate signaling via the Myocyte Enhancer Factor 2 (MEF2)/nuclear factor of activated T cell (NFAT) regulated genes. Ultimate consequences of these pathways include regulatory effects which alter the rate of transcription of the Na,K-ATPase β1 subunit gene atp1b1 by CREB, as well as by MEF2/NFAT.

Physical Activity Protects the Pathological Alterations of Alzheimer’s Disease Kidneys via the Activation of PACAP and BMP Signaling Pathways

“…The increased activity of AD mice augmented the expression of CREB and elevated the phosphorylation level of the transcription factor ( Figures 3B,C). CREB expression and specific localization in proximal tubules have been demonstrated earlier (Taub, 2018). In WT kidneys, CREB appears in the cytoplasm and shows an apical accumulation in proximal tubules; only cytoplasmic signals appeared in distal tubules and barely detectable CREB was visible in the Bowman capsule ( Figure 3D).…”

“…CREB phosphorylation can be harmed in AD and result in alterations of synaptic plasticity (Teich et al, 2015). CREB is an essential factor in the regulation of the Na-K ATPase function in kidney proximal tubules (Taub, 2018); subsequently, it regulates their filtration function. Elevated physical exercise increased the expression and phosphorylation of this transcription factor in AD kidneys.…”

Understanding the roles of salt-inducible kinases in cardiometabolic disease

“…Activated SIK1 phosphorylates PME-1 possibly at Ser72 ( Jaitovich and Bertorello, 2010 ), leading to its dissociation from the NKA/PP2A complex and allowing the dephosphorylation of NKA by PP2A to attain its catalytic activity ( Sjöström et al, 2007 ). In addition, NKA activity can be regulated at the gene expression levels ( Taub, 2018 ). The expression of ATP1B1 gene, encoding the NKA β1-subunit, is transcriptionally regulated by CRTCs ( Taub, 2018 ).…”

Salt Inducible Kinase Signaling Networks: Implications for Acute Kidney Injury and Therapeutic Potential

“…In this case, transcriptional regulation of the Na,K-ATPase β subunit gene atp1b1 becomes a critical determinant of the overall Na,K-ATPase level, and activity. The observed increase in the overall level of the Na,K-ATPase in the RPT cells following a prolonged incubation with PGE 2, can be explained by this type of regulation by the atp1b1 gene [35].…”