Molecular mechanisms for the modulation of blood pressure and potassium homeostasis by the distal convoluted tubule

Blood pressure (BP) follows a circadian rhythm, it increases on waking in the morning and decreases during sleeping at night. Disruption of the circadian BP rhythm has been reported to be associated with worsened cardiovascular and renal outcomes, however the underlying molecular mechanisms are still not clear. In this review, we briefly summarized the current understanding of the circadian BP regulation and provided therapeutic overview of the relationship between circadian BP rhythm and cardiovascular and renal health and disease.

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Abstract 066: The Undescribed Protein Caskin2 Is a Novel Regulator of eNOS Phosphorylation and Systemic Blood Pressure

Hypertension ◽

10.1161/hyp.66.suppl_1.066 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Sarah B Mueller ◽

Susan B Gurley ◽

Christopher D Kontos

Keyword(s):

Blood Pressure ◽

Molecular Mechanisms ◽

Systemic Blood Pressure ◽

Regulatory Subunit ◽

Systemic Blood ◽

Homologous Expression ◽

Ongoing Work ◽

Inducing Factors

Disruptions in the function of the quiescent endothelial cells (ECs) that line mature vessels can both result in and contribute to the progression of numerous cardiovascular diseases including hypertension, atherosclerosis, and disorders of vascular permeability. Despite recent attention, the signaling pathways that are active in quiescent ECs remain poorly characterized relative to those that regulate EC activation. In an effort to provide mechanistic insight into these pathways, we have characterized the previously undescribed protein Caskin2, which we hypothesize is a novel regulator of EC quiescence. Caskin2 is expressed in ECs throughout the vasculature, including the aorta, coronary arteries, and renal glomeruli. In vitro, Caskin2 promotes a quiescent EC phenotype characterized by decreased proliferation and increased resistance to apoptosis-inducing factors. Caskin2 knockout mice are viable and fertile. However, preliminary radiotelemetry measurements indicate that Caskin2 knockout (KO) mice have mildly elevated systemic blood pressure (BP). Compared to wild type (WT) littermates (n=8), Caskin2 KO mice (n=7) had increased mean arterial pressure (119+/-1 vs. 113+/-1, p=0.012), systolic BP (138+/-2 vs. 132+/-2, p=0.023), and diastolic BP (99+/-1 vs. 93+/-1, p=0.014) at baseline. To explore the molecular mechanisms of Caskin2’s effects, we used mass spectrometry to identify interacting proteins. Among the 67 proteins identified were the Ser/Thr phosphatase protein phosphatase 1 (PP1) and eNOS. Using standard in vitro biochemical techniques, we demonstrated that Caskin2 acts as a PP1 regulatory subunit. Interestingly, homologous expression of Caskin2 in vitro resulted in a marked increase in phosphorylation of eNOS on S1177, which is known to promote eNOS activity, and a decrease in phosphorylation on T495, which is associated with eNOS inhibition. Finally, PP1 has been shown to dephosphorylate eNOS T495 in vitro, suggesting a molecular mechanism for our in vivo findings. Ongoing work aims to determine if the interaction of Caskin2 and PP1 is required for the Caskin2-induced increase in activating phosphorylation of eNOS and to characterize the physiological mechanisms responsible for Caskin2’s effects on BP in more detail.

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Renal medullary 11β-hydroxysteroid dehydrogenase type 1 in Dahl salt-sensitive hypertension

Physiological Genomics ◽

10.1152/physiolgenomics.90283.2008 ◽

2008 ◽

Vol 36 (1) ◽

pp. 52-58 ◽

Cited By ~ 35

Author(s):

Yong Liu ◽

Ravinder J. Singh ◽

Kristie Usa ◽

Brian C. Netzel ◽

Mingyu Liang

Keyword(s):

Blood Pressure ◽

Urinary Excretion ◽

Molecular Mechanisms ◽

Renal Medulla ◽

Hydroxysteroid Dehydrogenase ◽

Induced Hypertension ◽

Intensive Investigation ◽

Salt Sensitive Hypertension ◽

Interfering Rna

The Dahl salt-sensitive rat is a widely used model of human salt-sensitive forms of hypertension. The kidney plays an important role in the pathogenesis of Dahl salt-sensitive hypertension, but the molecular mechanisms involved remain a subject of intensive investigation. Gene expression profiling studies suggested that 11β-hydroxysteroid dehydrogenase type 1 might be dysregulated in the renal medulla of Dahl salt-sensitive rats. Additional analysis confirmed that renal medullary expression of 11β-hydroxysteroid dehydrogenase type 1 was downregulated by a high-salt diet in SS-13BN rats, a consomic rat strain with reduced blood pressure salt sensitivity, but not in Dahl salt-sensitive rats. 11β-Hydroxysteroid dehydrogenase type 1 is known to convert inactive 11-dehydrocorticosterone to active corticosterone. The urinary corticosterone/11-dehydrocorticosterone ratio as well as urinary excretion of corticosterone was higher in Dahl salt-sensitive rats than in SS-13BN rats. Knockdown of renal medullary 11β-hydroxysteroid dehydrogenase type 1 with small-interfering RNA attenuated the early phase of salt-induced hypertension in Dahl salt-sensitive rats and reduced urinary excretion of corticosterone. Knockdown of 11β-hydroxysteroid dehydrogenase type 1 did not affect blood pressure in SS-13BN rats. Long-term attenuation of salt-induced hypertension was achieved with small hairpin RNA targeting renal medullary 11β-hydroxysteroid dehydrogenase type 1. In summary, we have demonstrated that suppression of 11β-hydroxysteroid dehydrogenase type 1 expression in the renal medulla attenuates salt-induced hypertension in Dahl salt-sensitive rats.

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Molecular and genetic aspects of guanylyl cyclase natriuretic peptide receptor-A in regulation of blood pressure and renal function

Physiological Genomics ◽

10.1152/physiolgenomics.00083.2018 ◽

2018 ◽

Vol 50 (11) ◽

pp. 913-928 ◽

Cited By ~ 10

Author(s):

Kailash N. Pandey

Keyword(s):

Blood Pressure ◽

Natriuretic Peptide ◽

Guanylyl Cyclase ◽

Natriuretic Peptides ◽

Molecular Mechanisms ◽

Phenotypic Characterization ◽

Natriuretic Peptide Receptor ◽

Peptide Receptor ◽

Natriuretic Peptide Receptor A ◽

Regulation Of Blood Pressure

Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and gene-targeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders.

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Molecular regulation of NKCC2 in the thick ascending limb

AJP Renal Physiology ◽

10.1152/ajprenal.00396.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. F1143-F1159 ◽

Cited By ~ 102

Author(s):

Gustavo R. Ares ◽

Paulo S. Caceres ◽

Pablo A. Ortiz

Keyword(s):

Blood Pressure ◽

Protein Interactions ◽

Membrane Trafficking ◽

Molecular Mechanisms ◽

Blood Pressure Regulation ◽

Renal Physiology ◽

Physical Factors ◽

Thick Ascending Limb ◽

Pressure Regulation ◽

Physiological Control

The kidney plays an essential role in blood pressure regulation by controlling short-term and long-term NaCl and water balance. The thick ascending limb of the loop of Henle (TAL) reabsorbs 25–30% of the NaCl filtered by the glomeruli in a process mediated by the apical Na+-K+-2Cl− cotransporter NKCC2, which allows Na+ and Cl− entry from the tubule lumen into TAL cells. In humans, mutations in the gene coding for NKCC2 result in decreased or absent activity characterized by severe salt and volume loss and decreased blood pressure (Bartter syndrome type 1). Opposite to Bartter's syndrome, enhanced NaCl absorption by the TAL is associated with human hypertension and animal models of salt-sensitive hypertension. TAL NaCl reabsorption is subject to exquisite control by hormones like vasopressin, parathyroid, glucagon, and adrenergic agonists (epinephrine and norepinephrine) that stimulate NaCl reabsorption. Atrial natriuretic peptides or autacoids like nitric oxide and prostaglandins inhibit NaCl reabsorption, promoting salt excretion. In general, the mechanism by which hormones control NaCl reabsorption is mediated directly or indirectly by altering the activity of NKCC2 in the TAL. Despite the importance of NKCC2 in renal physiology, the molecular mechanisms by which hormones, autacoids, physical factors, and intracellular ions regulate NKCC2 activity are largely unknown. During the last 5 years, it has become apparent that at least three molecular mechanisms determine NKCC2 activity. As such, membrane trafficking, phosphorylation, and protein-protein interactions have recently been described in TALs and heterologous expression systems as mechanisms that modulate NKCC2 activity. The focus of this review is to summarize recent data regarding NKCC2 regulation and discuss their potential implications in physiological control of TAL function, renal physiology, and blood pressure regulation.

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Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway

AJP Renal Physiology ◽

10.1152/ajprenal.00053.2013 ◽

2013 ◽

Vol 305 (5) ◽

pp. F645-F652 ◽

Cited By ~ 32

Author(s):

Benjamin Ko ◽

Abinash C. Mistry ◽

Lauren Hanson ◽

Rickta Mallick ◽

Brandi M. Wynne ◽

...

Keyword(s):

Blood Pressure ◽

Modern Society ◽

Surface Expression ◽

Distal Convoluted Tubule ◽

Sodium Balance ◽

Sodium Reabsorption ◽

Acute Effects ◽

Tubule Cell ◽

Sodium Chloride Cotransporter ◽

And Function

Hypertension is a leading cause of morbidity and mortality worldwide, and disordered sodium balance has long been implicated in its pathogenesis. Aldosterone is perhaps the key regulator of sodium balance and thus blood pressure. The sodium chloride cotransporter (NCC) in the distal convoluted tubule of the kidney is a major site of sodium reabsorption and plays a key role in blood pressure regulation. Chronic exposure to aldosterone increases NCC protein expression and function. However, more acute effects of aldosterone on NCC are unknown. In our salt-abundant modern society where chronic salt deprivation is rare, understanding the acute effects of aldosterone is critical. Here, we examined the acute effects (12–36 h) of aldosterone on NCC in the rodent kidney and in a mouse distal convoluted tubule cell line. Studies demonstrated that aldosterone acutely stimulated NCC activity and phosphorylation without affecting total NCC abundance or surface expression. This effect was dependent upon the presence of the mineralocorticoid receptor and serum- and glucocorticoid-regulated kinase 1 (SGK1). Furthermore, STE20/SPS-1-related proline/alanine-rich kinase (SPAK) phosphorylation also increased, and gene silencing of SPAK eliminated the effect of aldosterone on NCC activity. Aldosterone administration via a minipump in adrenalectomized rodents confirmed an increase in NCC phosphorylation without a change in NCC total protein. These data indicate that acute aldosterone-induced SPAK-dependent phosphorylation of NCC increases individual transporter activity.

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Diagnosis and Clinical Biochemistry of Inherited Tubulopathies

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456320103800503 ◽

2001 ◽

Vol 38 (5) ◽

pp. 459-470 ◽

Cited By ~ 13

Author(s):

J A Sayer ◽

S H S Pearce

Keyword(s):

Blood Pressure ◽

Biochemical Analysis ◽

Molecular Mechanisms ◽

Clinical Biochemistry ◽

Clinical History ◽

Tubular Epithelial Cell ◽

Renal Physiology ◽

Acid Base ◽

Functional Roles ◽

Serum And Urine

Epithelial ion channels and transporter proteins have physiologically important roles throughout the length of the nephron. Discovering the molecular identities of tubular epithelial cell proteins and their functional roles has increased understanding of both renal physiology and tubular diseases. Defects in tubular handling of solutes may present with nephrocalcinosis or nephrolithiasis, rickets, acid-base, electrolyte or blood pressure disturbances. Biochemical analysis of both serum and urine, together with clinical history and examination, remain fundamental for their diagnosis, whilst understanding of underlying molecular mechanisms allows appropriate management.

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