2015 Publications
Arriens, C., et al. (2015). "Placebo-controlled randomized clinical trial of fish oil's impact on fatigue, quality of life, and
disease activity in Systemic Lupus Erythematosus." Nutr J 14: 82.
INTRODUCTION: A recent metabolomic screen of sera from patients with Systemic Lupus Erythematosus
(SLE) found reduction of antioxidants and substrates for energy generation. These metabolic alterations may
underlie one of the most common features of SLE--fatigue. The metabolomic studies also noted reduced
omega-3 fatty acids, which are powerful anti- oxidants. This deficiency may be causally related to oxidative
stress, inflammation, disease activity, and fatigue in SLE. Supplementation of omega-3 fatty acids using fish
oil in SLE has been shown to reduce oxidative stress in other studies. The objective of this study is to
evaluate the effect of fish oil supplementation on clinical measures of fatigue, quality of life, and disease
activity as part of a randomized clinical trial. METHODS: Fifty SLE patients recruited in outpatient clinics were
randomized 1:1 to fish oil supplementation or olive oil placebo, and blinded to their treatment group. At
baseline and after 6 months of treatment, RAND Short Form-36 (RAND SF-36), Fatigue Severity Scale (FSS),
SLE Disease Activity Index (SLEDAI), and Physician Global Assessment (PGA) were completed; serum was also
collected for soluble mediator analysis. RESULTS: Thirty-two patients completed the study. PGA improved
significantly in the fish oil group compared with the placebo group (p = 0.015). The RAND SF-36 Energy
fatigue and Emotional well-being scores demonstrated improvement trends (p = 0.092 and 0.070). No clear
difference was seen in FSS and SLEDAI (p = 0.350 and p = 0.417). Erythrocyte sedimentation rate and serum
IL-12 were reduced (p = 0.008 and p = 0.058); while serum IL-13 was increased by fish oil supplementation
(p = 0.033). CONCLUSIONS: In this randomized, placebo-controlled 6-month trial, SLE patients randomized
to fish oil supplementation demonstrated improvement in their PGA, RAND SF-36, and some circulating
inflammatory markers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02021513 (registered 13
December 2013).
Babich, V. and F. Di Sole (2015). "The Na+/H+ Exchanger-3 (NHE3) Activity Requires Ezrin Binding to
Phosphoinositide and Its Phosphorylation." PLoS One 10(6): e0129306.
Na+/H+ exchanger-3 (NHE3) plays an essential role in maintaining sodium and fluid homeostasis in the
intestine and kidney epithelium. Thus, NHE3 is highly regulated and its function depends on binding to
multiple regulatory proteins. Ezrin complexed with NHE3 affects its activity via not well-defined
mechanisms. This study investigates mechanisms by which ezrin regulates NHE3 activity in epithelial
Opossum Kidney cells. Ezrin is activated sequentially by phosphatidylinositol-4,5-bisphosphate (PIP2)
binding and phosphorylation of threonine 567. Expression of ezrin lacking PIP2 binding sites inhibited NHE3
activity
(-40%) indicating that ezrin binding to PIP2 is required for preserving NHE3 activity. Expression of a
phosphomimetic ezrin mutated at the PIP2 binding region was sufficient not only to reverse NHE3 activity to
control levels but also to increase its activity (+80%) similar to that of the expression of ezrin carrying the
phosphomimetic mutation alone. Calcineurin Homologous Protein-1 (CHP1) is part, with ezrin, of the NHE3
regulatory complex. CHP1-mediated activation of NHE3 activity was blocked by expression of an ezrin
variant that could not be phosphorylated but not by an ezrin variant unable to bind PIP2. Thus, for NHE3
activity under baseline conditions not only ezrin phosphorylation, but also ezrin spatial-temporal targeting
on
the plasma membrane via PIP2 binding is required; however, phosphorylation of ezrin appears to
overcome the control of NHE3 transport. CHP1 action on NHE3 activity is not contingent on ezrin binding to
PIP2 but rather on ezrin phosphorylation. These findings are important in understanding the interrelation
and dynamics of a CHP1-ezrin-NHE3 regulatory complex.
Elias, B. C., et al. (2015). "Cdc42 regulates epithelial cell polarity and cytoskeletal function during kidney tubule
development." J Cell Sci 128(23): 4293-4305.
The Rho GTPase Cdc42 regulates key signaling pathways required for multiple cell functions, including
maintenance of shape, polarity, proliferation, migration, differentiation and morphogenesis. Although
previous studies have shown that Cdc42 is required for proper epithelial development and maintenance, its
exact molecular function in kidney development is not well understood. In this study, we define the specific
role of Cdc42 during murine kidney epithelial tubulogenesis by deleting it selectively at the initiation of
ureteric bud or metanephric mesenchyme development. Deletion in either lineage results in abnormal
tubulogenesis, with profound defects in polarity, lumen formation and the actin cytoskeleton. Ultimately,
these defects lead to renal failure. Additionally, in vitro analysis of Cdc42-null collecting duct cells shows
that Cdc42 controls these processes by regulating the polarity Par complex (Par3-Par6-aPKC-Cdc42) and the
cytoskeletal proteins N-Wasp and ezrin. Thus, we conclude that the principal role of Cdc42 in ureteric bud
and metanephric mesenchyme development is to regulate epithelial cell polarity and the actin cytoskeleton.
Hajarnis, S. S., et al. (2015). "Transcription Factor Hepatocyte Nuclear Factor-1beta (HNF-1beta) Regulates
MicroRNA-200 Expression through a Long Noncoding RNA." J Biol Chem 290(41): 24793-24805.
The transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) regulates tissue-specific gene
expression in the kidney and other epithelial organs. Mutations of HNF-1beta produce kidney cysts, and
previous studies have shown that HNF-1beta regulates the transcription of cystic disease genes, including
Pkd2 and Pkhd1. Here, we combined chromatin immunoprecipitation and next-generation sequencing
(ChIP-Seq) with microarray analysis to identify microRNAs (miRNAs) that are directly regulated by
HNF-1beta in renal epithelial cells. These studies identified members of the epithelial-specific miR-200
family (miR-200b/200a/429) as novel transcriptional targets of HNF-1beta. HNF-1beta binds to two
evolutionarily conserved sites located 28 kb upstream to miR-200b. Luciferase reporter assays showed that
the HNF-1beta binding sites were located within a promoter that was active in renal epithelial cells.
Mutations of the HNF-1beta binding sites abolished promoter activity. RT-PCR analysis revealed that a long
noncoding RNA (lncRNA) is transcribed from the promoter and encodes the miR-200 cluster. Inhibition of
the lncRNA with siRNAs decreased the levels of miR-200 but did not affect expression of the Ttll10 host
gene. The expression of the lncRNA and miR-200 was decreased in kidneys from HNF-1beta knock-out
mice and renal epithelial cells expressing dominant-negative mutant HNF-1beta. The expression of miR-200
targets, Zeb2 and Pkd1, was increased in HNF-1beta knock-out kidneys and in cells expressing mutant
HNF-1beta. Overexpression of miR-200 decreased the expression of Zeb2 and Pkd1 in HNF-1beta mutant
cells. These studies reveal a novel pathway whereby HNF-1beta directly contributes to the control of
miRNAs that are involved in epithelial-mesenchymal transition and cystic kidney disease.
Hajibeigi, A., et al. (2015). "Identification of novel regulatory NFAT and TFII-I binding elements in the calbindin-D28k
promoter in response to serum deprivation." Biochem Biophys Res Commun 465(3): 414-420.
Calbindin-D28k, a key regulator of calcium homeostasis plays a cytoprotective role in various tissues. We
used serum free (SFM) and charcoal stripped serum (csFBS) culture media as models of cellular stress to
modulate calbindin D28k expression and identify regulatory cis-elements and trans-acting factors in kidney
and beta cells. The murine calbindin-D28k promoter activity was significantly upregulated under SFM or
csFBS condition. Promoter analysis revealed evolutionary conserved regulatory cis-elements and deletion
of 23 nt from +117/+139 as critical for basal transcription. Bioinformatics analysis of the promoter revealed
conserved NFAT and TFII regulators elements. Forced expression of NFAT stimulated promoter activity.
Inhibition of NFAT transcriptional activity by FK506 attenuated calbindin-D28k expression. TFII-I was shown
to be necessary for basal promoter activity and to act cooperatively with NFAT. Using chromatin
immunoprecipitation (ChIP) assays, NFAT was shown to bind to both proximal and distal promoter regions.
ChIP assays also revealed recruitment of TFII to the -36/+139 region. Knockdown of TFII-I decreased
promoter activity. In summary, calbindin-D28k expression during serum deprivation is partly regulated by
NFAT and TF-II. This regulation may be important in vivo during ischemia and growth factor withdrawal to
regulate cellular function and maintenance.
Hedayati, S. S., et al. (2015). "Rationale and design of A Trial of Sertraline vs. Cognitive Behavioral Therapy for
End-stage Renal Disease Patients with Depression (ASCEND)." Contemp Clin Trials 47: 1-11.
Major Depressive Disorder (MDD) is highly prevalent in patients with End Stage Renal Disease (ESRD) treated
with maintenance hemodialysis (HD). Despite the high prevalence and robust data demonstrating an
independent association between depression and poor clinical and patient-reported outcomes, MDD is
under-treated when identified in such patients. This may in part be due to the paucity of evidence
confirming the safety and efficacy of treatments for depression in this population. It is also unclear whether
HD patients are interested in receiving treatment for depression. ASCEND (Clinical Trials Identifier Number
NCT02358343), A Trial of Sertraline vs. Cognitive Behavioral Therapy (CBT) for End-stage Renal Disease
Patients with Depression, was designed as a multi-center, 12-week, open-label, randomized, controlled trial
of prevalent HD patients with comorbid MDD or dysthymia. It will compare (1) a single Engagement
Interview vs. a control visit for the probability of initiating treatment for comorbid depression in up to 400
patients; and (2) individual chair-side CBT vs. flexible-dose treatment with a selective serotonin reuptake
inhibitor, sertraline, for improvement of depressive symptoms in 180 of the up to 400 patients. The
evolution of depressive symptoms will also be examined in a prospective longitudinal cohort of 90 HD
patients who choose not to be treated for depression. We discuss the rationale and design of ASCEND,
the first large-scale randomized controlled trial evaluating efficacy of non-pharmacologic vs.
pharmacologic treatment of depression in HD patients for patient-centered outcomes.
Hu, M. C., et al. (2016). "Renal Production, Uptake, and Handling of Circulating alphaKlotho." J Am Soc Nephrol 27(1):
79-90.
alphaKlotho is a multifunctional protein highly expressed in the kidney. Soluble alphaKlotho is released
through cleavage of the extracellular domain from membrane alphaKlotho by secretases to function as an
endocrine/paracrine substance. The role of the kidney in circulating alphaKlotho production and handling
is incompletely understood, however. Here, we found higher alphaKlotho concentration in suprarenal
compared with infrarenal inferior vena cava in both rats and humans. In rats, serum alphaKlotho
concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of
alphaKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous alphaKlotho in
anephric rats was four- to five-fold longer than that in normal rats, and exogenously injected labeled
recombinant alphaKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and
in vitro (proximal tubule cell line) studies showed that alphaKlotho traffics from the basal to the apical side
of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in alphaKlotho
homeostasis, producing and releasing alphaKlotho into the circulation and clearing alphaKlotho from the
blood into the urinary lumen.
Jain, N., et al. (2016). "Differences in Whole Blood Platelet Aggregation at Baseline and in Response to Aspirin and
Aspirin Plus Clopidogrel in Patients With Versus Without Chronic Kidney Disease." Am J Cardiol 117(4): 656-663.
Thrombotic events while receiving antiplatelet agents (APAs) are more common in subjects with versus
without chronic kidney disease (CKD). Data on antiplatelet effects of APA in CKD are scarce and limited by
lack of baseline platelet function before APA treatment. We hypothesized subjects with stages 4 to 5 CKD
versus no CKD have greater baseline platelet aggregability and respond poorly to aspirin and clopidogrel. In
a prospective controlled study, we measured whole blood platelet aggregation (WBPA) in 28 CKD and 16
non-CKD asymptomatic stable outpatients not on APA, frequency-matched for age, gender, obesity, and
diabetes mellitus. WBPA was remeasured after 2 weeks of each aspirin and aspirin plus clopidogrel. The
primary outcome was percent inhibition of platelet aggregation (IPA) from baseline. The secondary outcome
was residual platelet aggregability (RPA; proportion with <50% IPA). Baseline platelet aggregability was
similar between groups except adenosine diphosphate-induced WBPA, which was higher in CKD versus
non-CKD; median (interquartile range) = 13.5 (9.5 to 16.0) versus 9.0 (6.0 to 12.0) Omega, p = 0.007. CKD
versus non-CKD participants had lower clopidogrel-induced IPA, 38% versus 72%, p = 0.04. A greater
proportion of CKD versus non-CKD participants had RPA after clopidogrel treatment (56% vs 8.3%, p =
0.01). There were no significant interactions between CKD and the presence of cytochrome P450 2C19
polymorphisms for platelet aggregability in clopidogrel-treated participants. In conclusion, CKD versus
non-CKD subjects exhibited similar platelet aggregation at baseline, similar aspirin effects and greater RPA
on clopidogrel, which was independent of cytochrome P450 2C19 polymorphisms.
Lu, C. Y. and N. de Albuquerque Rocha (2015). "Oxidative Stress and Metabolism: The NF-Erythroid 2 p45-Related
Factor 2:Kelch-like ECH-Associated Protein 1 System and Regulatory T Lymphocytes in Ischemic AKI." J Am Soc
Nephrol 26(12): 2893-2895.
Mizuno, M., et al. (2015). "Aldosterone and Salt Loading Independently Exacerbate the Exercise Pressor Reflex in
Rats." Hypertension 66(3): 627-633.
The sympathetic and pressor responses to exercise are exaggerated in hypertension. Evidence suggests
that an overactive exercise pressor reflex (EPR) contributes to this abnormal responsiveness. The
mechanisms underlying this EPR overactivity are poorly understood. An increasing body of evidence
suggests that aldosterone and excessive salt intake play a role in regulating resting sympathetic activity
and blood pressure in hypertension. Therefore, each is a good candidate for the generation of EPR
dysfunction in this disease. The purpose of this study was to examine whether excessive salt intake and
chronic administration
of aldosterone potentiate EPR function. Changes in mean arterial pressure and renal sympathetic nerve
activity induced by EPR stimulation were examined in vehicle and aldosterone-treated (4 weeks via osmotic
mini-pump) Sprague-Dawley rats given either water or saline (elevated salt load) to drink. When compared
with vehicle/water-treated rats, stimulation of the EPR by muscle contraction evoked significantly greater
increases in mean arterial pressure in vehicle/saline, aldosterone/water, and aldosterone/saline-treated
animals (14+/-3, 29+/-3, 37+/-6, and 44+/-7 mm Hg/kg, respectively; P<0.01). A similar renal sympathetic
nerve activity response profile was likewise produced (39+/-11%, 87+/-15%, 110+/-20%, and 151+/-25%
kg, respectively; P<0.01). The pressor and sympathetic responses to the individual activation of the
mechanically and chemically sensitive components of the EPR were also augmented by both saline and
aldosterone. These data provide the first direct evidence that both aldosterone and high salt intake elicit
EPR overactivity. As such, each represents a potential mechanism by which sympathetic activity and blood
pressure are augmented during exercise in hypertension.
Neyra, J. A., et al. (2015). "Association of Hyperchloremia With Hospital Mortality in Critically Ill Septic Patients." Crit
Care Med 43(9): 1938-1944.
OBJECTIVES: Hyperchloremia is frequently observed in critically ill patients in the ICU. Our study aimed to
examine the association of serum chloride (Cl) levels with hospital mortality in septic ICU patients. DESIGN:
Retrospective cohort study. SETTING: Urban academic medical center ICU. PATIENTS: ICU adult patients
with severe sepsis or septic shock who had Cl measured on ICU admission were included. Those with
baseline estimated glomerular filtration rate less than 15 mL/min/1.73 m or chronic dialysis were excluded.
INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,940 patients included in the study, 615
patients (31.7%) had hyperchloremia (Cl >/= 110 mEq/L) on ICU admission. All-cause hospital mortality was
the dependent variable. Cl on ICU admission (Cl0), Cl at 72 hours (Cl72), and delta Cl (DeltaCl = Cl72 - Cl0)
were the independent variables. Those with Cl0 greater than or equal to 110 mEq/L were older and had
higher cumulative fluid balance, base deficit, and Sequential Organ Failure Assessment scores. Multivariate
analysis showed that higher Cl72 but not Cl0 was independently associated with hospital mortality in the
subgroup of patients with hyperchloremia on ICU admission (adjusted odds ratio for Cl72 per 5 mEq/L
increase = 1.27; 95% CI, 1.02-1.59; p = 0.03). For those who were hyperchloremic on ICU admission, every
within-subject 5 mEq/L increment in Cl72 was independently associated with hospital mortality (adjusted
odds ratio for DeltaCl 5 mEq/L = 1.37; 95% CI, 1.11-1.69; p = 0.003). CONCLUSIONS: In critically ill septic
patients manifesting hyperchloremia (Cl >/= 110 mEq/L) on ICU admission, higher Cl levels and
within-subject worsening hyperchloremia at 72 hours of ICU stay were associated with all-cause hospital
mortality. These associations were independent of base deficit, cumulative fluid balance, acute kidney injury,
and other critical illness parameters.
Pandey, A., et al. (2015). "Comparison of Morisky Medication Adherence Scale with therapeutic drug monitoring in
apparent treatment-resistant hypertension." J Am Soc Hypertens 9(6): 420-426 e422.
The Morisky Medication Adherence Scale (MMAS-8) is a questionnaire developed for screening of
non-adherence in patients with several chronic conditions, including uncomplicated hypertension. However,
its accuracy in predicting non-adherence in patients with apparent treatment-resistant hypertension (aTRH) is not known. Accordingly, we performed a retrospective study in 47 patients with a-TRH who had
completed the eight-item MMAS during the initial clinic visit. Non-adherence was defined as presence of
undetected serum levels of at least one prescribed antihypertensive drug by therapeutic drug monitoring.
We found that 26% of patients were considered to have low adherence score (<6), while the actual
prevalence of non-adherence was 51% by therapeutic drug monitoring. Sensitivity of the MMAS-8 was 26%
(95% confidence interval, 10.3%-48.4%) with specificity of 75% (95% confidence interval, 53.3%-90.2%). By
multivariate analysis, the MMAS-8 score was not an independent predictor of non-adherence, while certain
clinical parameters such as heart rate were found to be independent predictors of non-adherence. Our
study suggested limited accuracy of the MMAS-8 in detecting medication non-adherence in a-TRH.
Ravikumar, P., et al. (2015). "Nanoparticle facilitated inhalational delivery of erythropoietin receptor cDNA protects
against hyperoxic lung injury." Nanomedicine.
Our goals were to develop and establish nanoparticle (NP)-facilitated inhalational gene delivery, and to
validate its biomedical application by testing the hypothesis that targeted upregulation of pulmonary
erythropoietin receptor (EpoR) expression protects against lung injury. Poly-lactic-co-glycolic acid (PLGA)
NPs encapsulating various tracers were characterized and nebulizated into rat lungs. Widespread NP
uptake and distribution within alveolar cells were visualized by magnetic resonance imaging, and
fluorescent and electron microscopy. Inhalation of nebulized NPs bearing EpoR cDNA upregulated
pulmonary EpoR expression and downstream signal transduction (ERK1/2 and STAT5 phosphorylation) in
rats for up to 21days, and attenuated hyperoxia-induced damage in lung tissue based on apoptosis,
oxidative damage of DNA, protein and lipid, tissue edema, and alveolar morphology compared to vectortreated control animals. These results establish the feasibility and therapeutic efficacy of NP-facilitated
cDNA delivery to the lung, and demonstrate that targeted pulmonary EpoR upregulation mitigates acute
oxidative lung damage.
Shen, J., et al. (2015). "Novel source of human hematopoietic stem cells from peritoneal dialysis effluents." Stem Cell
Res 15(2): 299-304.
Hematopoietic stem cells (HSCs) hold great promise for the treatment of various diseases and blood
disorders. However, limited availability of these cells has hampered their applications in clinical and
biological research. Here we have identified a new source of autologous human HSCs in peritoneal dialysis
(PD) effluents from patients with end stage renal diseases (ESRDs). Cells isolated from PD effluents contain a
Lin-/CD34+/CD38-/CD90+ sub-population and can repopulate NOD/SCID/gamma-/- mice in serial
transplantation. Differing from cord blood HSCs, PD-derived HSCs have high tendencies to repopulate
peritoneal cavity and spleen with myeloid cells and B lymphocytes. Repopulating HSCs also reside in
peritoneal cavities in mice. The isolation of HSCs from peritoneal cavities provides a novel and promising
source of autologous and functional HSCs for stem cell research and possible clinical use.
Solow, E. B., et al. (2015). "Antinuclear Antibodies Are Associated With All-Cause Mortality and Cardiovascular
Outcomes in the General Population." J Am Coll Cardiol 65(24): 2669-2670.
Tanriover, B., et al. (2015). "Induction Therapies in Live Donor Kidney Transplantation on Tacrolimus and
Mycophenolate With or Without Steroid Maintenance." Clin J Am Soc Nephrol 10(6): 1041-1049.
BACKGROUND AND OBJECTIVES: Induction therapy with IL-2 receptor antagonist (IL2-RA) is
recommended as a first line agent in living donor renal transplantation (LRT). However, use of IL2-RA
remains controversial in LRT with tacrolimus (TAC)/mycophenolic acid (MPA) with or without steroids.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Organ Procurement and Transplantation
Network registry was studied for patients receiving LRT from 2000 to 2012 maintained on TAC/MPA at
discharge (n=36,153) to compare effectiveness of IL2-RA to other induction options. The cohort was
initially divided into two groups based on use of maintenance steroid at time of hospital discharge: steroid
(n=25,996) versus no-steroid (n=10,157). Each group was further stratified into three categories according
to commonly used antibody induction approach: IL2-RA, rabbit anti-thymocyte globulin (r-ATG), and noinduction in the steroid group versus IL2-RA, r-ATG and alemtuzumab in the no-steroid group. The main
outcomes were the risk of acute rejection at 1 year and overall allograft failure (graft failure or death) posttransplantation through the end of follow-up. Propensity score-weighted regression analysis was used to
minimize selection bias due to
non-random assignment of induction therapies. RESULTS: Multivariable logistic and Cox analysis adjusted
for propensity score showed that outcomes in the steroid group were similar between no-induction (odds
ratio [OR], 0.96; 95% confidence interval [95% CI], 0.86 to 1.08 for acute rejection; and hazard ratio [HR],
0.99; 95% CI, 0.90 to 1.08 for overall allograft failure) and IL2-RA categories. In the no-steroid group, odds of
acute rejection with r-ATG (OR, 0.73; 95% CI, 0.59 to 0.90) and alemtuzumab (OR, 0.53; 95% CI, 0.42 to 0.67)
were lower; however, overall allograft failure risk was higher with alemtuzumab (HR, 1.27; 95% CI, 1.03 to
1.56) but not with r-ATG (HR, 1.19; 95% CI, 0.97 to 1.45), compared with IL2-RA induction. CONCLUSIONS:
Compared with no-induction therapy, IL2-RA induction was not associated with better outcomes when TAC
MPA/steroids were used in LRT recipients. r-ATG appears to be an acceptable and possibly the preferred
induction alternative for IL2-RA in steroid-avoidance protocols.
Tientcheu, D., et al. (2015). "Target Organ Complications and Cardiovascular Events Associated With Masked
Hypertension and White-Coat Hypertension: Analysis From the Dallas Heart Study." J Am Coll Cardiol 66(20):
2159-2169.
BACKGROUND: Multiple epidemiological studies from Europe and Asia have demonstrated increased
cardiovascular risks associated with isolated elevation of home blood pressure (BP) or masked hypertension
(MH). Previous studies have not addressed cardiovascular outcomes associated with MH and white-coat
hypertension (WCH) in the general population in the United States. OBJECTIVES: The goal of this study was
to determine hypertensive target organ damage and adverse cardiovascular outcomes associated with
WCH (high clinic BP, >/=140/90 mm Hg; normal home BP, <135/85 mm Hg), MH (high home BP,
>/=135/85 mm Hg; normal clinic BP, <140/90 mm Hg), and sustained hypertension (high home and clinic
BP) in the DHS (Dallas Heart Study), a large, multiethnic, probability-based population cohort. METHODS:
Associations among WCH, MH, sustained hypertension, and aortic pulsed wave velocity by magnetic
resonance imaging; urinary albumin-to-creatinine ratio; and cystatin C were evaluated at study baseline.
Then, associations between WCH and MH with incident cardiovascular outcomes (coronary heart disease,
stroke, atrial fibrillation, heart failure, and cardiovascular death) over a median follow-up period of 9 years
were assessed. RESULTS: The study cohort comprised 3,027 subjects (50% African Americans). The sampleweighted prevalence rates of WCH and MH were 3.3% and 17.8%, respectively. Both WCH and MH were
independently associated with increased aortic pulsed wave velocity, cystatin C, and urinary
albumin-to-creatinine ratio. Both WCH (adjusted hazard ratio: 2.09; 95% confidence interval: 1.05 to 4.15)
and MH (adjusted hazard ratio: 2.03; 95% confidence interval: 1.36 to 3.03) were independently associated
with higher cardiovascular events compared with the normotensive group, even after adjustment for
traditional cardiovascular risk factors. CONCLUSIONS: In a multiethnic U.S. population, both WCH and MH
were independently associated with increased aortic stiffness, renal injury, and incident cardiovascular
events. Because MH is common and associated with an adverse cardiovascular profile, home BP
monitoring should be routinely performed among U.S. adults.
Toto, R. D. (2015). "From Phosphaturia to Cardiovascular Protection: Is Fibroblast Growth Factor-23 the Heart of the
Matter?" Circulation 132(1): 7-9.
Umetani, M. (2016). "Re-adopting classical nuclear receptors by cholesterol metabolites." J Steroid Biochem Mol Biol
157: 20-26.
Since the first cloning of the human estrogen receptor (ER) alpha in 1986 and the subsequent cloning of
human ERbeta, there has been extensive investigation of the role of estrogen/ER. Estrogens/ER play
important roles not only in sexual development and reproduction but also in a variety of other functions in
multiple tissues. Selective Estrogen Receptor Modulators (SERMs) are ER lignds that act as agonists or
antagonists depending on the target genes and tissues, and until recently, only synthetic SERMs have been
recognized. However, the discovery of the first endogenous SERM, 27-hydroxycholesterol (27HC), opened
a new dimension of ER action in health and disease. In addition to the identification of 27HC as a SERM,
oxysterols have been recently demonstrated as indirect modulators of ER through interaction with the
nuclear receptor Liver X Receptor (LXR) beta. In this review, the recent progress on these novel roles of
oxysterols in ER modulation is summarized.
Wu, Y., et al. (2015). "Two inwardly rectifying potassium channels, Irk1 and Irk2, play redundant roles in Drosophila
renal tubule function." Am J Physiol Regul Integr Comp Physiol 309(7): R747-756.
Inwardly rectifying potassium channels play essential roles in renal physiology across phyla. Bariumsensitive K(+) conductances are found on the basolateral membrane of a variety of insect Malpighian (renal)
tubules, including Drosophila melanogaster. We found that barium decreases the lumen-positive
transepithelial potential difference in isolated perfused Drosophila tubules and decreases fluid secretion
and transepithelial K(+) flux. In those insect species in which it has been studied, transcripts from multiple
genes encoding inwardly rectifying K(+) channels are expressed in the renal (Malpighian) tubule. In
Drosophila melanogaster, this includes transcripts of the Irk1, Irk2, and Irk3 genes. The role of each of these
gene products in renal tubule function is unknown. We found that simultaneous knockdown of Irk1 and Irk2
in the principal cell of the fly tubule decreases transepithelial K(+) flux, with no additive effect of Irk3
knockdown, and decreases barium sensitivity of transepithelial K(+) flux by approximately 50%. Knockdown
of any of the three inwardly rectifying K(+) channels individually has no effect, nor does knocking down Irk3
simultaneously with Irk1 or Irk2. Irk1/Irk2 principal cell double-knockdown tubules remain sensitive to the
kaliuretic effect of cAMP. Inhibition of the Na(+)/K(+)-ATPase with ouabain and Irk1/Irk2 double knockdown
have additive effects on
K(+) flux, and 75% of transepithelial K(+) transport is due to Irk1/Irk2 or ouabain-sensitive pathways. In
conclusion, Irk1 and Irk2 play redundant roles in transepithelial ion transport in the Drosophila
melanogaster renal tubule and are additive to Na(+)/K(+)-ATPase-dependent pathways.