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Author: Jakob Voelkl (56)


Dec
2017

Vascular calcification is a common phenomenon in patients with chronic kidney disease and strongly associated with increased cardiovascular mortality. Vascular calcification is an active process mediated in part by inflammatory processes in vascular smooth muscle cells (VSMC). These could be modified by the insufficient removal of proinflammatory cytokines through conventional high-flux (HF) membranes.

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Dec
2017

Mineralocorticoid receptor (MR) antagonism may affect bone turnover via direct and indirect pathways involving parathyroid hormone, but randomized controlled trials are lacking. In a pre-specified analysis of the "Eplerenone in primary hyperparathyroidism" placebo-controlled, randomized trial (ISRCTN 33941607), effects of eight weeks MR-blockade with eplerenone on bone turnover markers in 97 patients with primary hyperparathyroidism were tested. Mean age was 67.

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Dec
1969

Many pathophysiological processes are associated with proliferation, migration or death of distinct cell populations. Monitoring specific cell types and their progeny in a non-invasive, longitudinal and quantitative manner is still challenging. Here we show a novel cell-tracking system that combines Cre/lox-assisted cell fate mapping with a thymidine kinase (sr39tk) reporter gene for cell detection by positron emission tomography (PET).

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Dec
1969

TGFβ1, a decisive regulator of megakaryocyte maturation and platelet formation, has previously been shown to up-regulate both, store operated Ca2+ entry (SOCE) and Ca2+ extrusion by Na+/Ca2+ exchange. The growth factor thus augments the increase of cytosolic Ca2+ activity ([Ca2+]i) following release of Ca2+ from intracellular stores and accelerates the subsequent decline of [Ca2+]i. The effect on SOCE is dependent on a signaling cascade including p38 kinase, serum & glucocorticoid inducible kinase SGK1, and nuclear factor NFκB.

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May
2017

Vascular calcification resulting from hyperphosphatemia is a major determinant of mortality in chronic kidney disease (CKD). Vascular calcification is driven by aldosterone-sensitive osteogenic transformation of vascular smooth muscle cells (VSMCs). We show that even in absence of exogenous aldosterone, silencing and pharmacological inhibition (spironolactone, eplerenone) of the mineralocorticoid receptor (MR) ameliorated phosphate-induced osteo-/chondrogenic transformation of primary human aortic smooth muscle cells (HAoSMCs).

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Jun
2017

Primary hyperparathyroidism (pHPT) is associated with low-grade inflammation, left ventricular hypertrophy and increased cardiovascular mortality, but the association between inflammatory markers and parameters of adverse cardiac remodeling is unknown. We investigated the relationship between C-reactive protein (CRP), the essential amino acid tryptophan and its pro-inflammatory derivatives kynurenine and quinolinic acid (QUIN) with echocardiographic parameters.
Cross-sectional baseline data from the "Eplerenone in Primary Hyperparathyroidism" trial were analyzed.

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Dec
1969

Observational studies suggested a link between bone disease and left ventricular (LV) dysfunction that may be pronounced in hyperparathyroid conditions. We therefore aimed to test the hypothesis that circulating markers of bone turnover correlate with LV function in a cohort of patients with primary hyperparathyroidism (pHPT). Cross-sectional data of 155 subjects with pHPT were analyzed who participated in the "Eplerenone in Primary Hyperparathyroidism" (EPATH) Trial.

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Dec
1969

K7.1 voltage-gated potassium channels are expressed in vascular smooth muscle cells (VSMC) of diverse arteries, including mesenteric arteries. Based on pharmacological evidence using R-L3 (K7.

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Dec
1969

The progression of vascular calcification, an active process promoted by osteo/chondrogenic transformation of vascular smooth muscle cells (VSMCs) is attenuated by activation of the calcium-sensing receptor (CASR). Recent in-vitro studies revealed that vascular calcification could be blunted by Mg, but the underlying mechanisms remained elusive. The present study explored whether the effects of MgCl2 on vascular calcification involve the CASR.

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Dec
1969

Angiotensin-II is a key factor in renal fibrosis. Obstructive nephropathy induces an isoform shift from catalytic Ampkα2 towards Ampkα1 which contributes to signaling involved in renal tissue injury. The present study explored whether the Ampkα1 isoform contributes to the renal effects of angiotensin-II.

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Dec
1969

Klotho, a protein mainly expressed in kidney and cerebral choroid plexus, is a powerful regulator of 1,25(OH)2D3 formation. Klotho-deficient mice (kl/kl) suffer from excessive plasma 1,25(OH)2D3-, Ca(2+)- and phosphate-concentrations, leading to severe soft tissue calcification and accelerated aging. NH4Cl treatment prevents tissue calcification and premature ageing without affecting 1,25(OH)2D3-formation.

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Aug
2016

AMP-activated protein kinase (Ampk) regulates myocardial energy metabolism and plays a crucial role in the response to cell stress. In the failing heart, an isoform shift of the predominant Ampkα2 to the Ampkα1 was observed. The present study explored possible isoform specific effects of Ampkα1 in cardiomyocytes.

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Dec
1969

Accumulating evidence points toward mutual interaction between parathyroid hormone (PTH) and aldosterone as potential mechanism for increasing cardiovascular risk in primary hyperparathyroidism (pHPT).
The Eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism (EPATH) trial is a single-center, randomized, double-blind, parallel-group, placebo-controlled trial. The primary aim is to evaluate the effects of the mineralocorticoid receptor antagonist eplerenone on plasma intact PTH (iPTH) concentration in patients with pHPT.

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Dec
1969

Reduced homoarginine plasma levels are associated with unfavourable cardiovascular outcome in chronic kidney disease (CKD). Cardiovascular events in CKD are fostered by vascular calcification, an active process promoted by hyperphosphatemia and involving osteo-/chondrogenic transformation of vascular smooth muscle cells (VSMCs). The present study explored the effect of homoarginine on phosphate-induced osteo-/chondrogenic signalling and vascular calcification.

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Dec
1969

Klotho is required for the inhibitory effect of FGF23 on 1,25(OH)2D3 formation and Klotho-hypomorphic mice (kl/kl) suffer from severe tissue calcification due to excessive 1,25(OH)2D3 formation with subsequent increase of Ca2+ and phosphate concentrations and stimulation of osteogenic signaling. The excessive tissue calcification dramatically accelerates aging and leads to premature death of the animals. Osteogenic signaling in those mice is disrupted by treatment with NH4Cl, which prevents tissue calcification and early death of kl/kl mice.

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Jan
2016

Klotho, a protein counteracting aging, is a powerful inhibitor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] formation and regulator of mineral metabolism. In klotho hypomorphic (kl/kl) mice, excessive 1,25(OH)2D3 formation leads to hypercalcemia, hyperphosphatemia and vascular calcification, severe growth deficits, accelerated aging and early death. Kl/kl mice further suffer from extracellular volume depletion and hypotension, leading to the stimulation of antidiuretic hormone and aldosterone release.

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Nov
2015

A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt.

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Dec
1969

Excessive phosphate concentrations trigger vascular calcification, an active process promoted by osteoinduction of vascular smooth muscle cells (VSMCs) with increased expression and activity of transcription factor RUNX2 (Core-binding factor α1, CBFA1), alkaline phosphatase (ALPL), TGFß1, transcription factor NFAT5, and NFAT5-sensitive transcription factor SOX9. The osteoinductive signaling and vascular calcification of hyperphosphatemic klotho-hypomorphic mice could be reversed by treatment with NH4Cl, effects involving decrease of TGFß1 and inhibition of NFAT5-dependent osteoinductive signaling. Known effects of NH4Cl include alkalinization of acidic cellular compartments.

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Dec
1969

Consequences of obstructive nephropathy include tissue fibrosis, a major pathophysiological mechanism contributing to development of end-stage renal disease. Transforming growth factor β 1 (Tgfβ1) is involved in the progression of renal fibrosis. According to recent observations, ammonium chloride (NH4Cl) prevented phosphate-induced vascular remodeling, effects involving decrease of Tgfβ1 expression and inhibition of Tgfβ1-dependent signaling.

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Jan
2016

CD44 is required for signalling of macrophage migration inhibitory factor (MIF), an anti-apoptotic pro-inflammatory cytokine. MIF is expressed and released from blood platelets, key players in the orchestration of occlusive vascular disease. Nothing is known about a role of CD44 in the regulation of platelet function.

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Dec
1969

The serum- and glucocorticoid-inducible kinase SGK1 participates in the orchestration of cardiac hypertrophy and remodeling. Signaling linking SGK1 activity to cardiac remodeling is, however, incompletely understood. SGK1 phosphorylation targets include cyclin-dependent kinase inhibitor 1B (p27), a protein which suppresses cardiac hypertrophy.

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Jan
2016

Klotho, a protein expressed mainly in the kidney, is required for the inhibitory effect of FGF23 on renal 1,25(OH)2D3 formation. Klotho counteracts vascular calcification and diverse age-related disorders. Klotho-hypomorphic mice (kl/kl) suffer from severe vascular calcification and rapid aging.

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Dec
1969

AMP-activated protein kinase (Ampk) is a sensor of the cellular energy status and a powerful regulator of metabolism. Activation of Ampk was previously shown to participate in monocyte-to-fibroblast transition and matrix protein production in renal tissue. Thus, the present study explored whether the catalytic Ampkα1 isoform participates in the regulation of the renal fibrotic response following unilateral ureteral obstruction (UUO).

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Sep
2015

Homoarginine (hArg) is an endogenous, nonproteinogenic amino acid which differs from arginine by an additional methylene (CH2) group in the backbone. In this brief narrative review, we summarize the current literature on hArg in the renal and cardiovascular systems. Epidemiological studies have identified low hArg levels as an independent risk marker for cardiovascular, cerebrovascular, and renal diseases as well as for mortality.

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Dec
1969

Since the discovery of FGF23, secondary hyperparathyroidism (SHPT) in renal disease has been considered to result primarily from phosphorus retention rather than vitamin D deficiency. However, the impact of phosphorus restriction and vitamin D supplementation on SHPT is still ill defined.
We investigated the development of SHPT in a doxorubicin-induced proteinuric mouse model and tested different treatment strategies including a low phosphorus diet and substitution with native or active vitamin D in 129 S1/SvImJ wild-type mice.

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Jun
2015

Increased myocardial wall strain triggers the cardiac hypertrophic response by increasing cardiomyocyte size, reprogramming gene expression, and enhancing contractile protein synthesis. The LIM protein, migfilin, is a cytoskeleton-associated protein that was found to translocate in vitro into the nucleus in a Ca(2+)-dependent manner, where it co-activates the pivotal cardiac transcription factor Csx/Nkx2.5.

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Oct
2015

Klotho, a cofactor in suppressing 1,25(OH)2D3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH)2D3, Ca(2+), and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescence-associated molecules Tgfb1, Pai-1, p21, and Glb1.

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Mar
2015

Atherosclerosis, an inflammatory disease of arterial vessel walls, requires migration and matrix metalloproteinase (MMP)-9-dependent invasion of monocytes/macrophages into the vascular wall. MMP-9 expression is stimulated by transcription factor nuclear factor-κB, which is regulated by inhibitor κB (IκB) and thus IκB kinase. Regulators of nuclear factor-κB include serum- and glucocorticoid-inducible kinase 1 (SGK1).

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Dec
1969

Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling.

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Dec
1969

Shiga toxin 2 may trigger classical hemolytic uremic syndrome (HUS) eventually leading to renal failure. Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney is involved in the regulation of renal phosphate excretion and also retains renal protective effects. Renal failure is associated with renal depletion of klotho.

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Sep
2015

Duchenne muscular dystrophy (DMD) is a human genetic disease characterized by fibrosis and severe muscle weakness. Currently, there is no effective treatment available to prevent progressive fibrosis in skeletal muscles. The serum- and glucocorticoid-inducible kinase SGK1 regulates a variety of physiological functions and participates in fibrosis stimulation.

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Dec
1969

Vascular calcification is frequently found already in early stages of chronic kidney disease (CKD) patients and is associated with high cardiovascular risk. The process of vascular calcification is not considered a passive phenomenon but involves, at least in part, phenotypical transformation of vascular smooth muscle cells (VSMCs). Following exposure to excessive extracellular phosphate concentrations, VSMCs undergo a reprogramming into osteo-/chondroblast-like cells.

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Dec
1969

Fetuin-A (alpha-2-HS-glycoprotein, AHSG), a liver borne plasma protein, contributes to the prevention of soft tissue calcification, modulates inflammation, reduces insulin sensitivity and fosters weight gain following high fat diet or ageing. In polycystic ovary syndrome, fetuin-A levels correlate with free androgen levels, an observation pointing to androgen sensitivity of fetuin-A expression. The present study thus explored whether the expression of hepatic fetuin-A is modified by testosterone.

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Mar
2014

The PI 3-kinase (PI 3-K) signaling pathway is essential for Schwann cell myelination. Here we have characterized PI 3-K effectors activated during myelination by probing myelinating cultures and developing nerves with an antibody that recognizes phosphorylated substrates for this pathway. We identified a discrete number of phospho-proteins including the S6 ribosomal protein (S6rp), which is down-regulated at the onset of myelination, and N-myc downstream-regulated gene-1 (NDRG1), which is up-regulated strikingly with myelination.

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Feb
2014

Annexin A7 (Anxa7) is a cytoskeletal protein interacting with Ca(2+) signaling which in turn is a crucial factor for cardiac remodeling following cardiac injury. The present study explored whether Anxa7 participates in the regulation of cardiac stress signaling. To this end, mice lacking functional Anxa7 (anxa7(-/-)) and wild-type mice (anxa7(+/+)) were investigated following pressure overload by transverse aortic constriction (TAC).

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Dec
1969

Carbon monoxide (CO) interferes with cytochrome-dependent cellular functions and acts as gaseous transmitter. CO is released from CO-releasing molecules (CORM) including tricarbonyl-dichlororuthenium (II) dimer (CORM-2), molecules considered for the treatment of several disorders including vascular dysfunction, inflammation, tissue ischemia and organ rejection. Cytochrome P450-sensitive function include formation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) by renal 25-hydroxyvitamin D3 1-alpha-hydroxylase (Cyp27b1).

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Dec
1969

Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney, is required for the suppression of 1,25(OH)2D3-generating 25-hydroxyvitamin D3 1-alpha-hydroxylase (Cyp27b1) by FGF23. Conversely, 1,25(OH)2D3 stimulates, by activating the vitamin D3 receptor (Vdr), the expression of klotho, thus establishing a negative feedback loop. Klotho protects against renal and vascular injury.

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Dec
1969

Endothelial cell stiffness plays a key role in endothelium-dependent control of vascular tone and arterial blood pressure. Actin polymerization and distribution of microfilaments is essential for mechanical cell stiffness. Chorein, a protein encoded by the VPS13A gene, defective in chorea-acanthocytosis (ChAc), is involved in neuronal cell survival as well as cortical actin polymerization of erythrocytes and blood platelets.

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Dec
1969

The serum- and glucocorticoid-inducible kinase Sgk1 contributes to cardiac remodeling and development of heart failure, which is paralelled by Sgk1-dependent stimulation of the cardiac Na(+)/H(+) exchanger Nhe1. Glucocorticoids are powerful stimulators of Sgk1 expression and influence cardiac remodeling. The present study thus explored whether the glucocorticoid receptor agonist dexamethasone influenced cardiac Sgk1 expression, as well as activity, expression and phosphorylation at Ser(703) of the cardiac Na(+)/H(+) exchanger Nhe1.

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Jun
2013

Klotho, a hormone and enzyme, is a powerful regulator of ageing and life span. Klotho deficiency leads to cardiac arrythmia and sudden cardiac death. We thus explored whether klotho modifies cardiac K(+)-channel hERG.

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Jun
2013

Therapeutic potential of serum and glucocorticoid inducible kinase inhibition.

Expert Opin Investig Drugs 2013 Jun 19;22(6):701-14. Epub 2013 Mar 19.
Florian Lang, Jakob Voelkl
Expression of serum-and-glucocorticoid-inducible kinase-1 (SGK1) is low in most cells, but dramatically increases under certain pathophysiological conditions, such as glucocorticoid or mineralocorticoid excess, inflammation with TGFβ release, hyperglycemia, cell shrinkage and ischemia. SGK1 is activated by insulin and growth factors via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase and mammalian target of rapamycin. SGK1 sensitive functions include activation of ion channels (including epithelial Na(+) channel ENaC, voltage gated Na(+) channel SCN5A transient receptor potential channels TRPV4 - 6, Ca(2+) release activated Ca(2+) channel Orai1/STIM1, renal outer medullary K(+) channel ROMK, voltage gated K(+) channels KCNE1/KCNQ1, kainate receptor GluR6, cystic fibrosis transmembrane regulator CFTR), carriers (including Na(+),Cl(-) symport NCC, Na(+),K(+),2Cl(-) symport NKCC, Na(+)/H(+) exchangers NHE1 and NHE3, Na(+), glucose symport SGLT1, several amino acid transporters), and Na(+)/K(+)-ATPase.

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May
2013

Vascular calcification--is aldosterone a culprit?

Nephrol Dial Transplant 2013 May 8;28(5):1080-4. Epub 2013 Mar 8.
Florian Lang, Eberhard Ritz, Jakob Voelkl, Ioana Alesutan
In chronic kidney disease (CKD), increased plasma phosphate concentrations cause vascular calcification which substantially contribute to cardiovascular events and increased mortality of CKD patients. Similar to CKD patients, klotho-hypomorphic mice (kl/kl) also suffer from excessive vascular calcification leading to growth deficit, rapid ageing and early death. The hyperphosphataemia of kl/kl mice results from excessive formation of 1,25(OH)2D3 causing excessive intestinal phosphate absorption.

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Feb
2013

Klotho is a potent regulator of 1,25-hydroxyvitamin D3 [1,25(OH)2D3] formation and calcium-phosphate metabolism. Klotho-hypomorphic mice (kl/kl mice) suffer from severe growth deficits, rapid aging, hyperphosphatemia, hyperaldosteronism, and extensive vascular and soft tissue calcification. Sequelae of klotho deficiency are similar to those of end-stage renal disease.

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Dec
1969

Renal tissue fibrosis contributes to the development of end-stage renal disease. Causes for renal tissue fibrosis include obstructive nephropathy. The development of renal fibrosis following unilateral ureteral obstruction (UUO) is blunted in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1.

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Dec
1969

The voltage gated K(+) channel Kv1.5 participates in the repolarization of a wide variety of cell types. Kv1.

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Dec
1969

The oxidative stress-responsive kinase 1 (OSR1) participates in the WNK-(with no K) kinase dependent regulation of renal salt excretion and blood pressure. Little is known, however, about the role of OSR1 in the regulation of further renal transport systems. The present study analyzed the effect of OSR1 on NaPiIIa, the major renal tubular phosphate transporter.

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