title: Renal proximal tubule Na,K-ATPase is controlled by CREB-regulated transcriptional coactivators as well as salt-inducible kinase 1.
abstract: Sodium reabsorption by the kidney is regulated by locally produced natriuretic and anti-natriuretic factors, including dopamine and norepinephrine, respectively. Previous studies indicated that signaling events initiated by these natriuretic and anti-natriuretic factors achieve their effects by altering the phosphorylation of Na,K-ATPase in the renal proximal tubule, and that protein kinase A (PKA) and calcium-mediated signaling pathways are involved. The same signaling pathways also control the transcription of the Na,K-ATPase β subunit gene atp1b1 in renal proximal tubule cells. In this report, evidence is presented that (1) both the recently discovered cAMP-regulated transcriptional coactivators (CRTCs) and salt-inducible kinase 1 (SIK1) contribute to the transcriptional regulation of atp1b1 in renal proximal tubule (RPT) cells and (2) renal effectors, including norepinephrine, dopamine, prostaglandins, and sodium, play a role. Exogenously expressed CRTCs stimulate atp1b1 transcription. Evidence for a role of endogenous CRTCs includes the loss of transcriptional regulation of atp1b1 by a dominant-negative CRTC, as well as by a CREB mutant, with an altered CRTC binding site. In a number of experimental systems, SIK phosphorylates CRTCs, which are then sequestered in the cytoplasm, preventing their nuclear effects. Consistent with such a role of SIK in primary RPT cells, atp1b1 transcription increased in the presence of a dominant-negative SIK1, and in addition, regulation by dopamine, norepinephrine, and monensin was disrupted by a dominant-negative SIK1. These latter observations can be explained if SIK1 is phosphorylated and inactivated in the presence of these renal effectors. Our results support the hypothesis that Na,K-ATPase in the renal proximal tubule is regulated at the transcriptional level via SIK1 and CRTCs by renal effectors, in addition to the previously reported control of the phosphorylation of Na,K-ATPase.
authors.affiliation: Biochemistry Department,School of Medicine and Biomedical SciencesUniversity at Buffalo,140 Farber Hall, 3435 Main Street,Buffalo, NY 14214, USA. Electronic address: biochtau@buffalo.edu.
authors.forename: Mary
authors.initials: M
authors.lastname: Taub
authors.affiliation: Biochemistry Department,School of Medicine and Biomedical SciencesUniversity at Buffalo,140 Farber Hall, 3435 Main Street,Buffalo, NY 14214, USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Garimella
authors.affiliation: Biochemistry Department,School of Medicine and Biomedical SciencesUniversity at Buffalo,140 Farber Hall, 3435 Main Street,Buffalo, NY 14214, USA.
authors.forename: Dongwook
authors.initials: D
authors.lastname: Kim
authors.affiliation: Biochemistry Department,School of Medicine and Biomedical SciencesUniversity at Buffalo,140 Farber Hall, 3435 Main Street,Buffalo, NY 14214, USA.
authors.forename: Trivikram
authors.initials: T
authors.lastname: Rajkhowa
authors.affiliation: Biochemistry Department,School of Medicine and Biomedical SciencesUniversity at Buffalo,140 Farber Hall, 3435 Main Street,Buffalo, NY 14214, USA.
authors.forename: Facundo
authors.initials: F
authors.lastname: Cutuli
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D000316:Adrenergic alpha-Agonists; D017362:Cyclic AMP Response Element-Binding Protein; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D000254:Sodium-Potassium-Exchanging ATPase; D015232:Dinoprostone; D004298:Dopamine; D009638:Norepinephrine
keywords: CRTC; Dopamine; Na,K-ATPase; Norepinephrine; Prostaglandins; Renal proximal tubule; SIK1; Transcription