Kristen Solocinski

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.

The Circadian Clock in the Regulation of Renal Rhythms.

Since the kidney is integral to maintenance of fluid and ion homeostasis, and therefore blood pressure regulation, its proper function is paramount. Circadian fluctuations in blood pressure, renal blood flow, glomerular filtration rate, and sodium and water excretion have been documented for decades, if not longer. Recent studies on the role of circadian clock proteins in the regulation of a variety of renal transport genes suggest that the molecular clock in the kidney controls circadian fluctuations in renal function. The circadian clock appears to be a critical regulator of renal function with important implications for the treatment of renal pathologies, which include chronic kidney disease and hypertension. The development, regulation, and mechanism of the kidney clock are reviewed here.

Desoxycorticosterone pivalate‐salt treatment leads to non‐dipping hypertension in Per1 knockout mice

Increasing evidence demonstrates that circadian clock proteins are important regulators of physiological functions including blood pressure. An established risk factor for developing cardiovascular disease is the absence of a blood pressure dip during the inactive period. The goal of the present study was to determine the effects of a high salt diet plus mineralocorticoid on PER1‐mediated blood pressure regulation in a salt‐resistant, normotensive mouse model, C57BL/6J.

Renal Na Handling Defect Associated with PER1-Dependent Non-Dipping Hypertension In Male Mice

Many physiological functions have a circadian rhythm, including blood pressure (BP). BP is highest during the active phase, whereas during the rest period, BP dips 10-20%. Patients that do not experience this dip at night are termed nondippers. Nondipping hypertension is associated with increased risk of cardiovascular disease. The mechanisms underlying nondipping hypertension are not understood. Without the circadian clock gene Per1, C57BL/6J mice develop nondipping hypertension on a high-salt diet plus mineralocorticoid treatment (HS/DOCP). Our laboratory has shown that PER1 regulates expression of several genes related to sodium (Na) transport in the kidney, including epithelial Na channel (ENaC) and Na chloride cotransporter (NCC). Urinary Na excretion also demonstrates a circadian pattern with a peak during active periods. We hypothesized that PER1 contributes to circadian regulation of BP via a renal Na-handling-dependent mechanism. Na-handling genes from the distal nephron were inappropriately regulated in KO mice on HS/DOCP. Additionally, the night/day ratio of Na urinary excretion by Per1 KO mice is decreased compared with WT (4u2009×u2009vs. 7×, P < 0.001, n = 6 per group). Distal nephron-specific Per1 KO mice also show an inappropriate increase in expression of Na transporter genes αENaC and NCC. These results support the hypothesis that PER1 mediates control of circadian BP rhythms via the regulation of distal nephron Na transport genes. These findings have implications for the understanding of the etiology of nondipping hypertension and the subsequent development of novel therapies for this dangerous pathophysiological condition.

Circadian Regulation of Renal Function

The biological clock allows living organisms to anticipate periodic changes in the external environment and this feature allows a competitive advantage at both the species and individual level. Among the physiological parameters which need accurate adjustment during a 24-h period are fluid, electrolyte, acid–base balance, urine production, and maintenance of blood pressure. These functions are all mediated by the kidneys—organs that are critical for the regulation of blood pressure and the maintenance of body homeostasis. Developing evidence clearly demonstrates a role for the molecular circadian clock in the regulation of several renal ion transporters and channels with implications for circadian control of renal function.

The Circadian Clock in the Mammalian Kidney

Healthy circadian rhythms are important for maintaining overall health. Several core clock genes, including Bmal1, Per, CLOCK, and Cry encode transcription factors that regulate gene expression in the kidney and in nearly all other organs and cell types. Modulation of clock genes can cause major physiological effects. Loss of any of the core clock genes in mice results in significant changes in blood pressure, indicating that the molecular clock is critical for regulation of blood pressure. The kidney regulates electrolyte and volume balance and is thus an important regulator of blood pressure. Several lines of evidence suggest a role for the kidney clock in blood pressure regulation.

Development of hypertension – clinical impact of dysregulation of circadian rhythms and implications for treatment

Blood pressure, like most physiological processes, exhibits a circadian pattern of variation. Disruption of the normal circadian rhythm of blood pressure is associated with end organ damage and increased risk of adverse cardiovascular outcomes. In this review, we discuss the role of the renin angiotensin aldosterone system and the molecular clock in main- taining circadian blood pressure patterns. We also consider disrupted circadian blood pressure rhythms and hypertension in distinct populations and the role of chronotherapy in the treatment