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Navarro V.M.,Diabetes and Hypertension | Bosch M.A.,Oregon Health And Science University | Leon S.,University of Cordoba, Spain | Leon S.,Institute Salud Carlos III | And 14 more authors.
Endocrinology | Year: 2015

Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r-/- mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreasedLHrelease in ovariectomized-sham replaced females, as documented forNK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons andGnRHneurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons. Copyright © 2015 by the Endocrine Society.


Pham P.-T.T.,University of California at Los Angeles | Edling K.L.,Diabetes and Hypertension | Chakkera H.A.,Mayo Clinic Hospital | Pham P.-C.T.,View Medical
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy | Year: 2012

New-onset diabetes mellitus after transplantation (NODAT) is a serious and common complication following solid organ transplantation. NODAT has been reported in 2% to 53% of all solid organ transplants. Kidney transplant recipients who develop NODAT have variably been reported to be at increased risk of fatal and nonfatal cardiovascular events and other adverse outcomes including infection, reduced patient survival, graft rejection, and accelerated graft loss compared with those who do not develop diabetes. Limited clinical studies in liver, heart, and lung transplants similarly suggested that NODAT has an adverse impact on patient and graft outcomes. Early detection and management of NODAT must, therefore, be integrated into the treatment of transplant recipients. Studies investigating the best screening or predictive tool for identifying patients at risk for developing NODAT early after transplantation, however, are lacking. We review the clinical predictive values of fasting plasma glucose, oral glucose tolerance test, and A1C in assessing the risk for NODAT development and as a screening tool. Simple diabetes prediction models that incorporate clinical and/or metabolic risk factors (such as age, body mass index, hyper triglyceridemia, or metabolic syndrome) are also presented. © 2012 Pham et al, publisher and licensee Dove Medical Press Ltd.


Vaidya A.,Diabetes and Hypertension | Vaidya A.,Brigham and Women's Hospital | Vaidya A.,Harvard University | Curhan G.C.,Brigham and Women's Hospital | And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Hypertension is associated with higher PTH levels, and specific antihypertensive medications may modulate PTH. Whether hypertension or the use of specific antihypertensive medications influences the risk of developing incident primary hyperparathyroidism (P-HPTH) is not known. Objective: The purpose of this study was to investigate whether a history of hypertension and the use of specific antihypertensive medications determine the risk for developing P-HPTH in a large prospective study. Design/Participants: A longitudinal prospective cohort of female nurses in the Nurses' Health Study I(n = 75 600), who did not have P-HPTH at baseline and completed a questionnaire assessment of lifetime history of P-HPTH were followed from 1986 to 2008. Most participants were white and postmenopausal. Setting: The study was a nationwide cohort study. Main Outcome Measure: Incident P-HPTH was assessed initially via questionnaire and then was confirmed by medical record review. Cox proportional hazards models were used to adjust for potential confounders. Results: We documented 347 incident cases of P-HPTH during 1 719 416 person-years of follow-up. The age-adjusted relative risk (RR) for incident P-HPTH associated with hypertension was 1.80 (95% confidence interval [CI], 1.43-2.26), and the multivariate-adjusted RR was 1.45 (95% CI, 1.10-1.91). Among participants with a history of hypertension, the use of furosemide, when compared with the use of other antihypertensive medications, was associated with increased risk for developing P-HPTH; age-adjusted RR for incident P-HPTH was 1.79 (95% CI, 1.15-2.79) and multivariate-adjusted RR was 1.71 (95% CI, 1.08-2.71). Conclusions: In a large longitudinal prospective cohort study of mostly older white women, a history of hypertension and use of furosemide were associated with a significantly higher risk of developing P-HPTH. Copyright © 2015 by the Endocrine Society.


Lee C.,University of Southern California | Zeng J.,University of Southern California | Drew B.G.,Diabetes and Hypertension | Sallam T.,University of California at Los Angeles | And 7 more authors.
Cell Metabolism | Year: 2015

Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome. © 2015 Elsevier Inc.


Beaven S.W.,Howard Hughes Medical Institute | Matveyenko A.,Diabetes and Hypertension | Matveyenko A.,University of California at Los Angeles | Wroblewski K.,Howard Hughes Medical Institute | And 8 more authors.
Cell Metabolism | Year: 2013

Liver X receptors (LXRs) regulate lipogenesis and inflammation, but their contribution to the metabolic syndrome is unclear. We show that LXRs modulate key aspects of the metabolic syndrome in mice. LXRαβ-deficient-ob/ob (LOKO) mice remain obese but show reduced hepatic steatosis and improved insulin sensitivity compared to ob/ob mice. Impaired hepatic lipogenesis in LOKO mice is accompanied by reciprocal increases in adipose lipid storage, reflecting tissue-selective effects on the SREBP, PPARγ, and ChREBP lipogenic pathways. LXRs are essential for obesity-driven SREBP-1c and ChREBP activity in liver, but not fat. Furthermore, loss of LXRs in obesity promotes adipose PPARγ and ChREBP-β activity, leading to improved insulin sensitivity. LOKO mice also exhibit defects in β cell mass and proliferation despite improved insulin sensitivity. Our data suggest that sterol sensing by LXRs in obesity is critically linked with lipid and glucose homeostasis and provide insight into the complex relationships between LXR and insulin signaling. © 2013 Elsevier Inc.


PubMed | U.S. National Institute on Aging, Diabetes and Hypertension, University of Southern California and University of California at Los Angeles
Type: Journal Article | Journal: Cell metabolism | Year: 2015

Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome.


Saxena A.R.,Diabetes and Hypertension | Karumanchi S.A.,Beth Israel Deaconess Medical Center | Brown N.J.,Vanderbilt University | Royle C.M.,Beth Israel Deaconess Medical Center | And 2 more authors.
Hypertension | Year: 2010

Pregnancies complicated by new-onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear whether this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high-and low-sodium balance. Ten women had a history of hypertensive pregnancy (5 with preeclampsia; 5 with transient hypertension of pregnancy), and 15 women had a history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone, and soluble fms-like tyrosine kinase 1 levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with a history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 versus 104 mm Hg and 73 versus 65 mm Hg, respectively; P<0.05). Women with a history of hypertensive pregnancy had a pressor response to salt loading, demonstrated by an increase in systolic blood pressure on a high-salt diet. They also had greater systolic pressor response (10 versus 2 mm Hg; P=0.03), greater increase in aldosterone (56.8 versus 30.8 ng/dL; P=0.03), and increase in soluble fms-like tyrosine kinase 1 levels (11.0 versus-18.9 pg/mL; P=0.02) after infusion of angiotensin II in low-sodium balance compared with controls. Thus, women with a history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal, and soluble fms-like tyrosine kinase 1 responses to infused angiotensin II in low-sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women. Copyright © 2010 American Heart Association. All rights reserved.


Babwah A.V.,University of Western Ontario | Babwah A.V.,Lawson Health Research Institute | Pampillo M.,University of Western Ontario | Pampillo M.,Lawson Health Research Institute | And 5 more authors.
Endocrinology | Year: 2012

The kisspeptin receptor (KISS1R) is a Gαq/11-coupled seven-transmembrane receptor activated by a group of peptides referred to as kisspeptins (Kps). The Kp/KISS1R signaling system is a powerful regulator of GnRH secretion, and inactivating mutations in this system are associated with hypogonadotropic hypogonadism. A recent study revealed that Kp triggers prolonged signaling; not from the inability of the receptor to undergo rapid desensitization, but instead from the maintenance of a dynamic and active pool of KISS1R at the cell surface. To investigate this further, we hypothesized that if a dynamic pool of receptor is maintained at the cell surface for a protracted period, chronic Kp-10 treatment would trigger the sustained activation of Gαq/11 as evidenced through the prolonged activation of phospholipase C, protein kinase C, and prolonged mobilization of intracellular Ca2+. Through single-cell analyses, we tested our hypothesis in human embryonic kidney (HEK) 293 cells and found that was indeed the case. We subsequently determined that prolonged KISS1R signaling was not a phenomenon specific to HEK 293 cells but is likely a conserved property of KISS1R-expressing cells because evidence of sustained KISS1R signaling was also observed in the GT1-7 GnRH neuronal and Chinese hamster ovary cell lines. While exploring the regulation of prolonged KISS1R signaling, we identified a critical role for extracellular Ca2+. We found that although free intracellular Ca2+, primarily derived from intracellular stores, was sufficient to trigger the acute activation of a major KISS1R secondary effector, protein kinase C, it was insufficient to sustain chronic KISS1R signaling; instead extracellular Ca2+ was absolutely required for this. Copyright © 2012 by The Endocrine Society.


Garza A.E.,Diabetes and Hypertension | Rariy C.M.,Diabetes and Hypertension | Sun B.,Diabetes and Hypertension | Williams J.S.,Diabetes and Hypertension | And 12 more authors.
Hypertension | Year: 2015

Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor's rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7-20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure. © 2014 American Heart Association, Inc.


Kikic Z.,Medical University of Vienna | Regele H.,Medical University of Vienna | Nordmeyer V.,Medical University of Vienna | Wahrmann M.,Medical University of Vienna | And 3 more authors.
Transplantation | Year: 2011

Background. Although diffuse linear C4d deposition in peritubular capillaries (PTCs) is a well-established criterion of alloantibody-mediated kidney transplant rejection, the actual relevance of focal or granular C4d deposits or staining outside PTC (glomeruli and arterioles) has yet to be established. Methods. This study was designed to evaluate the diagnostic significance of such nontypical C4d staining patterns. A total of 539 early indication biopsies (329 kidney transplants) were analyzed by immunohistochemistry using a polyclonal anti-C4d antibody. Results. We found a close interrelationship between diffuse or focal linear C4d deposition in PTC, linear endothelial deposition in glomeruli, and arteriolar C4d. These specific patterns were also related to transplant glomerulitis and recipient presensitization. No such associations, however, were observed for other patterns, such as granular C4d in PTC. Detection of diffuse but not focal linear C4d in PTC was found to be associated with adverse allograft survival (5-year death-censored graft survival: 48% vs. 82%, 89%, or 84% in patients with focal, minimal, or no C4d, respectively; P<0.0001). Univariate analysis also revealed inferior graft survival in recipients with linear C4d in glomeruli (P=0.02). Applying multivariate Cox regression analysis, however, only diffuse linear PTC staining was found to be predictive of graft loss (hazard ratio 3.95 [95% confidence interval 1.62-9.60]; P=0.002). Conclusion. There might be a relationship between humoral alloimmunity and distinct less established staining patterns, such as focal linear C4d in PTC, endothelial C4d in glomeruli, or arteriolar C4d. Nevertheless, our results reemphasize the prognostic value of diffuse linear PTC staining. Copyright © 2011 by Lippincott Williams & Wilkins.

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