Transcriptional regulation of NHE3 and SGLT1 by the circadian clock protein Per1 in proximal tubule cells.
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.
['Solocinski|Kristen|K|', 'Richards|Jacob|J|', 'All|Sean|S|', 'Cheng|Kit-Yan|KY|', 'Khundmiri|Syed J|SJ|', 'Gumz|Michelle L|ML|']
D021581:Active Transport, Cell Nucleus D000818:Animals D001665:Binding Sites D056926:CLOCK Proteins D048149:Casein Kinase 1 epsilon D048148:Casein Kinase Idelta D002460:Cell Line D005786:Gene Expression Regulation D006801:Humans D007687:Kidney Tubules, Proximal D008297:Male D057507:Mice, 129 Strain D018345:Mice, Knockout D056950:Period Circadian Proteins D011401:Promoter Regions, Genetic D011743:Pyrimidines D034622:RNA Interference D012333:RNA, Messenger D051269:Sodium-Glucose Transporter 1 D000074083:Sodium-Hydrogen Exchanger 3 D017923:Sodium-Hydrogen Exchangers D000254:Sodium-Potassium-Exchanging ATPase D013997:Time Factors D014158:Transcription, Genetic D014162:Transfection
transcription kidney Na+-glucose cotransporter 1 Na+/H+ exchanger gene regulation period 1 renal sodium reabsorption