Regulation of renal proximal tubule function by CREB‐regulated transcriptional coactivators and salt‐inducible kinase

Abstract

The kidney plays a central role in blood pressure regulation, via its ability to control sodium reabsorption via locally produced natriuretic, and anti‐natriuretic factors. Previously, natriuretic and anti‐natriuretic factors, including dopamine and norepinephrine, have been observed to alter sodium reabsorption by changing the phosphorylation state of Na,K‐ATPase in the renal proximal tubule (RPT). Protein Kinase A and calcium‐mediated signaling pathways are involved. These same signaling pathways control transcription of the Na,K‐ATPase β subunit gene atp1b1 in RPT cells. In this report, evidence is presented that (1) recently discovered cAMP‐regulated transcriptional coactivators (CRTCs), and salt‐inducible kinase 1 (SIK1) contribute to the transcriptional regulation of atp1b1 in RPT cells and (2) renal effectors, including norepinephrine, dopamine, prostaglandins, and sodium, play a role. Evidence for the role of CRTCs includes the loss of transcriptional regulation of atp1b1 by a dominant‐negative CRTC, and a CREB mutant with an altered CRTC binding site. In a number of experimental systems, SIK1 phosphorylates CRTCs, which are then sequestered in the cytoplasm, preventing their nuclear effects. Consistent with such a role of SIK1 in primary RPT cells, atp1b1 transcription increased in the presence of a dominant‐negative SIK1. Regulation by dopamine, norepinephrine, and monensin was also disrupted by a dominant‐negative SIK1. These latter observations can be explained if these renal effectors phosphorylate and inactivate SIK1. Our results support the hypothesis that Na,K‐ATPase in the RPT is regulated at the transcriptional level via SIK1 and CRTCs, in addition to the previously reported control of the phosphorylation of Na,K‐ATPase.Support or Funding InformationNHLBI