title: Transcriptional regulation of NHE3 and SGLT1 by the circadian clock protein Per1 in proximal tubule cells.
abstract: We have previously demonstrated that the circadian clock protein period (Per)1 coordinately regulates multiple genes involved in Na(+) reabsorption in renal collecting duct cells. Consistent with these results, Per1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. The proximal tubule is responsible for a majority of Na(+) reabsorption. Previous work has demonstrated that expression of Na(+)/H(+) exchanger 3 (NHE3) oscillates with a circadian pattern and Na(+)-glucose cotransporter (SGLT)1 has been demonstrated to be a circadian target in the colon, but whether these target genes are regulated by Per1 has not been investigated in the kidney. The goal of the present study was to determine if Per1 regulates the expression of NHE3, SGLT1, and SGLT2 in the kidney. Pharmacological blockade of nuclear Per1 entry resulted in decreased mRNA expression of SGLT1 and NHE3 but not SGLT2 in the renal cortex of mice. Per1 small interfering RNA and pharmacological blockade of Per1 nuclear entry in human proximal tubule HK-2 cells yielded the same results. Examination of heterogeneous nuclear RNA suggested that the effects of Per1 on NHE3 and SGLT1 expression occurred at the level of transcription. Per1 and the circadian protein CLOCK were detected at promoters of NHE3 and SGLT1. Importantly, both membrane and intracellular protein levels of NHE3 and SGLT1 were decreased after blockade of nuclear Per1 entry. This effect was associated with reduced activity of Na(+)-K(+)-ATPase. These data demonstrate a role for Per1 in the transcriptional regulation of NHE3 and SGLT1 in the kidney.
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida; and.
authors.forename: Kristen
authors.initials: K
authors.lastname: Solocinski
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida; and.
authors.forename: Jacob
authors.initials: J
authors.lastname: Richards
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida;
authors.forename: Sean
authors.initials: S
authors.lastname: All
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida;
authors.forename: Kit-Yan
authors.initials: KY
authors.lastname: Cheng
authors.affiliation: Department of Physiology and Biophysics, Howard University College of Medicine, Washington, District of Columbia.
authors.forename: Syed J
authors.initials: SJ
authors.lastname: Khundmiri
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida; and Michelle.Gumz@medicine.ufl.edu.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Gumz
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: C539022:PER1 protein, human; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; C495674:SLC5A1 protein, human; C000613385:SLC9A3 protein, human; C495675:Slc5a1 protein, mouse; C000613386:Slc9a3 protein, mouse; D051269:Sodium-Glucose Transporter 1; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C522839:PF-670462; D056926:CLOCK Proteins; C538943:CLOCK protein, human; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Na+-glucose cotransporter 1; Na+/H+ exchanger; gene regulation; kidney; period 1; renal sodium reabsorption; transcription