TY  - JOUR
AB  - AIM: Vascular calcification (VC), a characteristic feature of peripheral artery disease in patients with diabetes and chronic kidney disease, has been associated with poor prognosis. We hypothesize that hyperglycemia drives VC through alterations in metabolomic and transcriptomic profiles. METHODS: Human coronary artery smooth muscle cells (SMCs) were cultured with 0, 5.5, and 25 mM glucose under calcifying conditions. Untargeted metabolomic and transcriptomic analyses were performed at different time points. Mitochondrial respiration was examined using Seahorse analysis. RESULTS: Glucose-treated SMCs promoted extracellular matrix (ECM) calcification in a concentration- and time-dependent manner. The absence of glucose entirely abolished SMC calcification but reduced SMC proliferation in control and calcifying conditions compared to 25 mM glucose. Multi-omics data integration revealed key players from the hypotaurine/taurine metabolic pathway as the center hub of the reconstructed network. Glucose promoted the hypotaurine secretion, while its intracellular abundance was not altered. Blocking hypotaurine production by propargylglycine increased ECM calcification, while hypotaurine treatment prevented it. Furthermore, omics data suggest energy remodeling in calcifying SMCs under hyperglycemia. Calcifying SMCs exhibited decreased oxygen consumption that was partially restored by hypotaurine. Validation of our in vitro models using the murine warfarin model demonstrated reduced hypotaurine/taurine transporter (TAUT) expression in SMCs. CONCLUSIONS: Our multi-omics analysis revealed a role of the hypotaurine/taurine metabolic pathway in glucose-induced SMC calcification. Moreover, our data suggest a glucose-dependent energy remodeling in calcifying SMCs and that increasing glucose concentrations fuel ECM calcification. Our work highlights potential novel therapeutic targets that warrant further investigation in hyperglycemia-dependent in vitro SMC calcification.
AU  - Heuschkel, M.A.*
AU  - Jaminon, A.*
AU  - Gräber, S.*
AU  - Artati, A.
AU  - Adamski, J.
AU  - Jankowski, J.*
AU  - Schurgers, L.*
AU  - Marx, N.*
AU  - Jahnen-Dechent, W.*
AU  - Goettsch, C.*
C1  - 75084
C2  - 57746
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Hypotaurine reduces glucose-mediated vascular calcification.
JO  - Acta Physiol.
VL  - 241
IS  - 8
PB  - Wiley
PY  - 2025
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - AIM: In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. However, apart from case reports, there is no evidence favoring ENaC blockade in patients with NS. METHODS: The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/day, max. 15 mg/day) in comparison to standard therapy with the loop diuretic furosemide (40 mg/day, max. 120 mg/day) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (BCM, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (12.5 mg/day, max. 25 mg/day). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size. RESULTS: Median baseline OH was +26.4 (interquartile range 15.5-35.1)% extracellular water (ECW) in the amiloride arm and + 27.9 (24.1-29.4)% ECW in the furosemide arm and decreased by 1.95 (0.80-6.40) and 5.15 (0.90-8.30)% ECW after 8 days, respectively, and by 10.10 (1.30-14.40) and 7.40 (2.80-10.10)% ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms. CONCLUSION: The AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Further studies are required to better define the role of amiloride in NS (EudraCT 2019-002607-18).
AU  - Schork, A.
AU  - Vogel, E.
AU  - Bohnert, B.N.
AU  - Essigke, D.
AU  - Wörn, M.
AU  - Fischer, I.*
AU  - Heyne, N.
AU  - Birkenfeld, A.L.
AU  - Artunc, F.
C1  - 70784
C2  - 55892
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Amiloride versus furosemide for the treatment of edema in patients with nephrotic syndrome: A pilot study (AMILOR).
JO  - Acta Physiol.
VL  - 240
IS  - 8
PB  - Wiley
PY  - 2024
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - AIM: The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections. METHODS: We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (RestGTi) in which Rest was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups. RESULTS: We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity. CONCLUSION: The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.
AU  - Vitale, C.*
AU  - Natali, G.*
AU  - Cerullo, M.S.*
AU  - Floss, T.
AU  - Michetti, C.*
AU  - Grasselli, G.*
AU  - Benfenati, F.*
C1  - 70493
C2  - 55635
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - The homeostatic effects of the RE-1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse.
JO  - Acta Physiol.
VL  - 240
IS  - 6
PB  - Wiley
PY  - 2024
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - The circadian clock is a hierarchical timing system regulating most physiological and behavioral functions with a period of approximately 24 hours in humans and other mammalian species. The circadian clock drives daily eating rhythms that, in turn, reinforce the circadian clock network itself to anticipate and orchestrate metabolic responses to food intake. Eating is tightly interconnected with the circadian clock and recent evidence shows that the timing of meals is crucial for the control of appetite and metabolic regulation. Obesity results from combined long-term dysregulation in food intake (homeostatic and hedonic circuits), energy expenditure, and energy storage. Increasing evidence supports that the loss of synchrony of daily rhythms significantly impairs metabolic homeostasis and is associated with obesity. This review presents an overview of mechanisms regulating food intake (homeostatic/hedonic) and focuses on the crucial role of the circadian clock on the metabolic response to eating, thus providing a fundamental research axis to maintain a healthy eating behavior.
AU  - Chamorro, R.*
AU  - Jouffe, C.
AU  - Oster, H.*
AU  - Uhlenhaut, N.H.
AU  - Meyhöfer, S.M.*
C1  - 67199
C2  - 54212
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - When should I eat: A circadian view on food intake and metabolic regulation.
JO  - Acta Physiol.
VL  - 237
IS  - 3
PB  - Wiley
PY  - 2023
SN  - 1748-1708
ER  - 

TY  - JOUR
AU  - Weigert, C.
C1  - 67861
C2  - 54339
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - The post-exercise paradox of reduced glucose tolerance and insulin sensitivity.
JO  - Acta Physiol.
VL  - 238
IS  - 4
PB  - Wiley
PY  - 2023
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - Sodium retention and edema are hallmarks of nephrotic syndrome (NS). Different experimental rodent models have been established for simulating NS, however, not all of them feature sodium retention which requires proteinuria to exceed a certain threshold. In rats, puromycin aminonucleoside nephrosis (PAN) is a classic NS model introduced in 1955 that was adopted as doxorubicin-induced nephropathy (DIN) in 129S1/SvImJ mice. In recent years, mice with inducible podocin deletion (Nphs2Δipod ) or podocyte apotosis (POD-ATTAC) have been developed. In these models, sodium retention is thought to be caused by activation of the epithelial sodium channel (ENaC) in the distal nephron through aberrantly filtered serine proteases or proteasuria. Strikingly, rodent NS models follow an identical chronological time course after development of proteinuria featuring sodium retention within days and spontaneous reversal thereafter. In DIN and Nphs2Δipod mice, inhibition of ENaC by amiloride or urinary serine protease activity by aprotinin prevents sodium retention, opening up new and promising therapeutic approaches that could be translated into the treatment of nephrotic patients. However, the essential serine protease(s) responsible for ENaC activation is (are) still unknown. With the use of nephrotic rodent models, there is the possibility that this (these) will be identified in the future. This review summarizes the various rodent models used to study experimental nephrotic syndrome and the insights gained from these models with regard to the pathophysiology of sodium retention.
AU  - Xiao, M.*
AU  - Bohnert, B.N.
AU  - Grahammer, F.*
AU  - Artunc, F.
C1  - 64991
C2  - 52604
TI  - Rodent models to study sodium retention in experimental nephrotic syndrome.
JO  - Acta Physiol.
VL  - 235
IS  - 3
PY  - 2022
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - AIM: The serine protease prostasin (Prss8) is expressed in the distal tubule and stimulates proteolytic activation of the epithelial sodium channel (ENaC) in co-expression experiments in vitro. The aim of this study was to explore the role of prostasin in proteolytic ENaC activation in the kidney in vivo. METHODS: We used genetically modified knockin mice carrying a Prss8 mutation abolishing proteolytic activity (Prss8-S238A) or a mutation leading to a zymogen-locked state (Prss8-R44Q). Mice were challenged with low sodium diet and diuretics. Regulation of ENaC activity by Prss8-S238A and Prss8-R44Q was studied in vitro using the Xenopus laevis oocyte expression system. RESULTS: Co-expression of murine ENaC with Prss8-wt or Prss8-S238A in oocytes caused maximal proteolytic ENaC activation, whereas ENaC was activated only partially in oocytes co-expressing Prss8-R44Q. This was paralleled by a reduced proteolytic activity at the cell surface of Prss8-R44Q expressing oocytes. Sodium conservation under low sodium diet was preserved in Prss8-S238A and Prss8-R44Q mice but with higher plasma aldosterone concentrations in Prss8-R44Q mice. Treatment with the ENaC inhibitor triamterene over four days was tolerated in Prss8-wt and Prss8-S238A mice, whereas Prss8-R44Q mice developed salt wasting and severe weight loss associated with hyperkalemia and acidosis consistent with impaired ENaC function and renal failure. CONCLUSION: Unlike proteolytically inactive Prss8-S238A, zymogen-locked Prss8-R44Q produces incomplete proteolytic ENaC activation in vitro and causes a severe renal phenotype in mice treated with the ENaC inhibitor triamterene. This indicates that Prss8 plays a role in proteolytic ENaC activation and renal function independent of its proteolytic activity.
AU  - Essigke, D.*
AU  - Ilyaskin, A.V.*
AU  - Wörn, M.*
AU  - Bohnert, B.N.
AU  - Xiao, M.*
AU  - Daniel, C.*
AU  - Amann, K.*
AU  - Birkenfeld, A.L.
AU  - Szabo, R.*
AU  - Bugge, T.H.*
AU  - Korbmacher, C.*
AU  - Artunc, F.
C1  - 61463
C2  - 50272
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Zymogen-locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice.
JO  - Acta Physiol.
VL  - 232
IS  - 1
PB  - Wiley
PY  - 2021
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - Aim Resistance exercise increases muscle mass over time. However, the early signalling events leading to muscle growth are not yet well-defined. Here, we aim to identify new signalling pathways important for muscle remodelling after exercise.Methods We performed a phosphoproteomics screen after a single bout of exercise in mice. As an exercise model we used unilateral electrical stimulation in vivo and treadmill running. We analysed muscle biopsies from human subjects to verify if our findings in murine muscle also translate to exercise in humans.Results We identified a new phosphorylation site on Myocardin-Related Transcription Factor B (MRTF-B), a co-activator of serum response factor (SRF). Phosphorylation of MRTF-B is required for its nuclear translocation after exercise and is accompanied by the transcription of the SRF target gene Fos. In addition, high-intensity exercise also remodels chromatin at specific SRF target gene loci through the phosphorylation of histone 3 on serine 10 in myonuclei of both mice and humans. Ablation of the MAP kinase member MSK1/2 is sufficient to prevent this histone phosphorylation, reduce induction of SRF-target genes, and prevent increases in protein synthesis after exercise.Conclusion Our results identify a new exercise signalling fingerprint in vivo, instrumental for exercise-induced protein synthesis and potentially muscle growth.
AU  - Solagna, F.*
AU  - Nogara, L.*
AU  - Dyar, K.A.
AU  - Greulich, F.*
AU  - Mir, A.A.
AU  - Türk, C.*
AU  - Bock, T.*
AU  - Geremia, A.*
AU  - Baraldo, M.*
AU  - Sartori, R.*
AU  - Farup, J.*
AU  - Uhlenhaut, N.H.
AU  - Vissing, K.*
AU  - Krüger, M.*
AU  - Blaauw, B.*
C1  - 59116
C2  - 48573
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Exercise-dependent increases in protein synthesis are accompanied by chromatin modifications and increased MRTF-SRF signalling.
JO  - Acta Physiol.
VL  - 230
IS  - 1
PB  - Wiley
PY  - 2020
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - Aim: Sodium retention is the hallmark of nephrotic syndrome (NS) and mediated by the proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases. Plasmin is highly abundant in nephrotic urine and has been proposed to be the principal serine protease responsible for ENaC activation in NS. However, a proof of the essential role of plasmin in experimental NS is lacking. Methods: We used a genetic mouse model of NS based on an inducible podocin knockout (Bl6-Nphs2tm3.1Antc*Tg(Nphs1-rtTA*3G)8Jhm*Tg(tetO-cre)1Jaw or nphs2Δipod). These mice were crossed with plasminogen deficient mice (Bl6-Plgtm1Jld or plg−/−) to generate double knockout mice (nphs2Δipod*plg−/−). NS was induced after oral doxycycline treatment for 14 days and mice were followed for subsequent 14 days. Results: Uninduced nphs2Δipod*plg−/− mice had normal kidney function and sodium handling. After induction, proteinuria increased similarly in both nphs2Δipod*plg+/+ and nphs2Δipod*plg−/− mice. Western blot revealed the urinary excretion of plasminogen and plasmin in nphs2Δipod*plg+/+ mice which were absent in nphs2Δipod*plg−/− mice. After the onset of proteinuria, amiloride-sensitive natriuresis was increased compared to the uninduced state in both genotypes. Subsequently, urinary sodium excretion dropped in both genotypes leading to an increase in body weight and development of ascites. Treatment with the serine protease inhibitor aprotinin prevented sodium retention in both genotypes. Conclusions: This study shows that mice lacking urinary plasminogen are not protected from ENaC-mediated sodium retention in experimental NS. This points to an essential role of other urinary serine proteases in the absence of plasminogen.
AU  - Xiao, M.*
AU  - Bohnert, B.N.
AU  - Aypek, H.*
AU  - Kretz, O.*
AU  - Grahammer, F.*
AU  - Aukschun, U.*
AU  - Wörn, M.*
AU  - Janessa, A.*
AU  - Essigke, D.*
AU  - Daniel, C.*
AU  - Amann, K.*
AU  - Huber, T.B.*
AU  - Plow, E.F.*
AU  - Birkenfeld, A.L.
AU  - Artunc, F.
C1  - 59206
C2  - 48664
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome.
JO  - Acta Physiol.
VL  - 231
IS  - 1
PB  - Wiley
PY  - 2020
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - Sodium retention and extracellular volume expansion are typical features of patients with nephrotic syndrome. In recent years, from in vitro data, endoluminal activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases has been proposed as an underlying mechanism. Recently, this concept was supported in vivo in nephrotic mice that were protected from proteolytic ENaC activation and sodium retention by the use of aprotinin for the pharmacological inhibition of urinary serine protease activity. These and other findings from studies in both rodents and humans highlight the impact of active proteases in the urine, or proteasuria, on ENaC-mediated sodium retention and edema formation in nephrotic syndrome. Targeting proteasuria could become a therapeutic approach to treat patients with nephrotic syndrome. However, pathophysiologically relevant proteases remain to be identified. In this review, we introduce the concept of proteasuria to explain tubular sodium avidity and conclude that proteasuria can be considered as a key mechanism of sodium retention in patients with nephrotic syndrome.
AU  - Artunc, F.
AU  - Wörn, M.*
AU  - Schork, A.
AU  - Bohnert, B.N.
C1  - 55318
C2  - 45045
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Proteasuria-the impact of active urinary proteases on sodium retention in nephrotic syndrome.
JO  - Acta Physiol.
VL  - 225
IS  - 4
PB  - Wiley
PY  - 2019
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - Aim In nephrotic syndrome, aberrantly filtered plasminogen (plg) is converted to active plasmin by tubular urokinase-type plasminogen activator (uPA) and thought to lead to sodium retention by proteolytic activation of the epithelial sodium channel (ENaC). This concept predicts that uPA is an important factor for sodium retention and that inhibition of uPA might be protective in nephrotic syndrome. Methods Activation of amiloride-sensitive currents by uPA and plg were studied in Xenopus laevis oocytes expressing murine ENaC. In doxorubicin-induced nephrotic mice, uPA was inhibited pharmacologically by amiloride and genetically by the use of uPA-deficient mice (uPA(-/-)). Results Experiments in Xenopus laevis oocytes expressing murine ENaC confirmed proteolytic ENaC activation by a combination of plg and uPA which stimulated amiloride-sensitive currents with concomitant cleavage of the ENaC gamma-subunit at the cell surface. Treatment of nephrotic wild-type mice with amiloride inhibited urinary uPA activity, prevented urinary plasmin formation and sodium retention. In nephrotic mice lacking uPA (uPA(-/-)), urinary plasmin formation from plg was suppressed and urinary uPA activity absent. However, in nephrotic uPA(-/-) mice, sodium retention was not reduced compared to nephrotic uPA(+/+) mice. Amiloride prevented sodium retention in nephrotic uPA(-/-) mice which confirmed the critical role of ENaC in sodium retention. Conclusion uPA is responsible for the conversion of aberrantly filtered plasminogen to plasmin in the tubular lumen in vivo. However, uPA-dependent plasmin generation is not essential for ENaC-mediated sodium retention in experimental nephrotic syndrome.
AU  - Bohnert, B.N.
AU  - Daiminger, S.*
AU  - Wörn, M.*
AU  - Sure, F.*
AU  - Staudner, T.*
AU  - Ilyaskin, A.V.*
AU  - Batbouta, F.*
AU  - Janessa, A.*
AU  - Schneider, J.C.*
AU  - Essigke, D.*
AU  - Kanse, S.*
AU  - Haerteis, S.*
AU  - Korbmacher, C.*
AU  - Artunc, F.
C1  - 55902
C2  - 46692
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Urokinase-type plasminogen activator (uPA) is not essential for epithelial sodium channel (ENaC)-mediated sodium retention in experimental nephrotic syndrome.
JO  - Acta Physiol.
VL  - 227
IS  - 4
PB  - Wiley
PY  - 2019
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - We welcome the opportunity to reply to the elegant editorial of Prof. Ehmke 1 in which he highlights contradicting conclusions reached by Hinrichs et al. 2 and by us 3 in two recently published articles in Acta Physiologica. In our reply, we first comment on some technical aspects discussed by Prof. Ehmke as possible explanations for the discrepant conclusions reached in the two studies. In addition, we highlight some in vivo data reported by Hinrichs et al. 2 which in our view do not oppose but rather support our conclusion that urokinase, also known as urokinase-type plasminogen activator (uPA), is not essential for sodium retention in nephrotic syndrome.
AU  - Bohnert, B.N.
AU  - Kanse, S.*
AU  - Haerteis, S.*
AU  - Korbmacher, C.*
AU  - Artunc, F.
C1  - 57495
C2  - 47819
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Rebuttal to editorial: Sodium retention by uPA in nephrotic syndrome?
JO  - Acta Physiol.
PB  - Wiley
PY  - 2019
SN  - 1748-1708
ER  - 

TY  - JOUR
AU  - Ertürk, A.
C1  - 57341
C2  - 47687
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Cellular and molecular probing of intact human organs.
JO  - Acta Physiol.
VL  - 227
PB  - Wiley
PY  - 2019
SN  - 1748-1708
ER  - 

TY  - JOUR
AU  - Rubio-Aliaga, I.*
AU  - Daryadel, A.*
AU  - Ruiz, P.A.*
AU  - Gehring, N.*
AU  - Fuente, R.*
AU  - Stojanovic, D.*
AU  - Ugrica, M.*
AU  - Bettoni, C.*
AU  - Sabrautzki, S.
AU  - Pastor-Arroyo, E.M.*
AU  - Frey-Wagner, I.*
AU  - Lorenz-Depiereux, B.
AU  - Diener, S.
AU  - Gil-Pena, H.*
AU  - Michalke, B.
AU  - Strom, T.M.
AU  - Hrabě de Angelis, M.
AU  - Rogler, G.*
AU  - Santos, F.*
AU  - Wagner, C.A.*
C1  - 57340
C2  - 47688
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Constitutive activation of Jak1 leads to increased fibroblast growth factor 23 levels in mice.
JO  - Acta Physiol.
VL  - 227
PB  - Wiley
PY  - 2019
SN  - 1748-1708
ER  - 

TY  - JOUR
AU  - Ziesak, V.*
AU  - Rohde, M.*
AU  - Birkenfeld, A.L.
AU  - Koehling, R.*
C1  - 57342
C2  - 47686
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Effect of sodium-dicarboxylate cotransporter on CA1 pyramidal cells, synaptic transmission and hippocampal network activity.
JO  - Acta Physiol.
VL  - 227
PB  - Wiley
PY  - 2019
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - AimRecent work has demonstrated that activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases causes sodium retention in nephrotic syndrome. The aim of this study was to elucidate a potential role of plasma kallikrein (PKLK) as a candidate serine protease in this context.MethodsWe analysed PKLK in the urine of patients with chronic kidney disease (CKD, n=171) and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in PKLK-deficient mice (klkb1(-/-)) with experimental nephrotic syndrome induced by doxorubicin injection.ResultsIn patients with CKD, we found that PKLK is excreted in the urine up to a concentration of 2gmL(-1) which was correlated with albuminuria (r=.71) and overhydration as assessed by bioimpedance spectroscopy (r=.44). PKLK increased ENaC-mediated whole-cell currents, which was associated with the appearance of a 67kDa -ENaC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in -ENaC prevented channel stimulation by PKLK. In a mouse model for nephrotic syndrome, active PKLK was present in nephrotic urine of klkb1(+/+) but not of klkb1(-/-) mice. However, klkb1(-/-) mice were not protected from ENaC activation and sodium retention compared to nephrotic klkb1(+/+) mice.ConclusionPlasma kallikrein is detected in the urine of proteinuric patients and mice and activates ENaC invitro involving the putative prostasin cleavage site. However, PKLK is not essential for volume retention in nephrotic mice.
AU  - Haerteis, S.*
AU  - Schork, A.
AU  - Doerffel, T.*
AU  - Bohnert, B.N.
AU  - Nacken, R.*
AU  - Woern, M.*
AU  - Xiao, M.*
AU  - Essigke, D.*
AU  - Janessa, A.*
AU  - Schmaier, A.H.*
AU  - Feener, E.P.*
AU  - Häring, H.-U.
AU  - Bertog, M.*
AU  - Korbmacher, C.*
AU  - Artunc, F.
C1  - 54171
C2  - 45321
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Plasma kallikrein activates the epithelial sodium channel invitro but is not essential for volume retention in nephrotic mice.
JO  - Acta Physiol.
VL  - 224
IS  - 1
PB  - Wiley
PY  - 2018
SN  - 1748-1708
ER  - 

TY  - JOUR
AU  - Götz, S.
AU  - Rauser, B.
AU  - Brodski, C.*
AU  - Prakash, N.*
C1  - 48404
C2  - 41068
CY  - Hoboken
TI  - Early and localized expression of ion channels and ion channel subunits in the developing mesodiencephalic dopaminergic domain of the mouse embryo.
JO  - Acta Physiol.
VL  - 216
PB  - Wiley-blackwell
PY  - 2016
SN  - 1748-1708
ER  - 

TY  - JOUR
AB  - Rationale: in COPD. We previously reported that senescent cells are increased in lungs from patients with COPD and express a robust senescence-associated secretory phenotype (SASP), which is proinflammatory. Here, we investigated whether lung cell senescence in COPD was related to overactivation of the mTOR (mechanistic target of rapamycin) signaling pathway and whether targeting this pathway inhibited cell senescence and/or suppressed the SASP in COPD. To assess the link between mTOR activation and cellular senescence in lung specimens and derived cultured Objectives: pulmonary-endothelial cells (P-ECs)and pulmonary artery smooth muscle cells (PA-SMCs) from patients with COPD and age- and sex-matched control smokers; to use a new mouse model that allows mTOR activation in targeted cells and determine whether this activation induces cell senescence. Strong activation of the mTOR-Akt signaling pathway was found in lungs from patients with COPD compared to Methods and Results: controls, with a marked PTEN decrease and activation of mTOR complex 1 (mTORC1) substrates S6K and 4EBP, and of mTORC2 substrates P-Akt and GSK3, together with an increase in p21 and p16 protein levels. Similar activation of the mTORC1 and mTORC2 substrates 473 were found in cultured PA-SMCs and P-ECs from patients with COPD compared to controls. Cultured P-ECs or PA-SMCs from patients with COPD exhibited an early onset of cell senescence as assessed by a decrease in the number of population doubling (PDLs) and an increase in beta-gal-positive cells. Treatment of the cells from patients with COPD with rapamycin (10 nM) normalized the number of PDLs to that seen in controls and decreased the number of beta-gal-positive cells. Treatment with rapamycin also increased PDLs in cells from controls but to a lesser extent than in those from patients with COPD. No such effects were seen after cell exposure to a selective S6-kinase inhibitor. Rapamycin reduced IL6 and other cytokine levels released by senescent cells. Cultured PA-SMCs from SM22-TSC1-/- mice, which exhibited strong mTORC1 activation in PA-SMCs, were characterized by an early onset of cell senescence compared to control mice, which was delayed by cell exposure to rapamycin. These results show that the increased propensity of lung cells to senescence in COPD is related to overactivation of the mTOR Conclusion: signaling pathway and can be suppressed by low doses of rapamycin.
AU  - Houssaini, A.
AU  - Kebe, K.*
AU  - Breau, M.*
AU  - Marcos, E.*
AU  - Abid, S.*
AU  - Bizard, E.*
AU  - Huang, J.*
AU  - Attwe, A.*
AU  - Rideau, D.*
AU  - Validire, P.*
AU  - Maitre, B.*
AU  - Amsellem, V.*
AU  - Meiners, S.
AU  - Adnot, S.*
C1  - 49215
C2  - 40693
CY  - Hoboken
SP  - 142-143
TI  - Targeting the mtor signaling pathway to inhibit lung cell senescence in Chronic Obstructive Pulmonary Disease (COPD).
JO  - Acta Physiol.
VL  - 217
PB  - Wiley-blackwell
PY  - 2016
SN  - 1748-1708
ER  - 

TY  - JOUR
AU  - Solimena, M.
C1  - 48405
C2  - 41067
CY  - Hoboken
TI  - Insulin granule biogenesis and turnover.
JO  - Acta Physiol.
VL  - 216
PB  - Wiley-blackwell
PY  - 2016
SN  - 1748-1708
ER  - 

TY  - JOUR
AU  - Dimou, L.
C1  - 31655
C2  - 34610
CY  - Hoboken
SP  - 20
TI  - Heterogeneity of NG2-glia: Its role and impact in the adult brain.
JO  - Acta Physiol.
VL  - 210
PB  - Wiley-Blackwell
PY  - 2014
SN  - 1748-1708
ER  -