-
[show abstract]
[hide abstract]
ABSTRACT: Die Funktion der Niere wird ganz wesentlich durch die Aktivität von Ionenkanälen und Ionentransportern bestimmt. Auf dem Gebiet
der Ionenkanalforschung hat es in den vergangenen zehn Jahren einige herausragende Neuentdeckungen gegeben, die das Feld der
Kanalopathien, also Erkrankungen die auf die Fehlfunktion von einzelnen Ionenkanälen zurückzuführen sind, ganz neu beleuchtet
haben und gleichzeitig auch die pathophysiologische Bedeutung von Ionenkanälen für multifaktorielle Erkrankungen aufzeigten.
Diese Entwicklung betrifft insbesondere auch das nephrologische Forschungsgebiet, bei der Arbeiten zu Ionenkanälen nicht nur
Fortschritte im Verständnis der physiologischen Nierenfunktion, sondern besonders auch bei der Aufklärung von Pathomechanismen
von spezifischen Nierenerkrankungen ergeben haben. Anhand von fünf Nieren- und Hochdruckerkrankungen wird die Art und Weise,
in der Ionenkanäle Krankheiten auslösen können, dargestellt.
Renal function is essentially determined by ion channels and ion transporters. Several outstanding discoveries have been made
in the past 10years in the field of research on ion channels. These insights have shed new light on ion channelopathies,
i.e., disorders due to dysfunction of individual ion channels, and at the same time pinpointed the pathophysiological significance
of ion channels for multifactorial diseases. This development also applies particularly to the area of nephrological research
where studies on ion channels have not only led to progress in understanding physiological renal function but have also aided
in elucidating the pathomechanisms of specific kidney diseases. Illustrated on the basis of five renal and hypertensive diseases,
the manner in which ion channels can cause disease is described.
Der Nephrologe 04/2012; 3(5):358-365.
-
F Mahfoud,
O Vonend,
H Bruck,
W Clasen,
S Eckert,
B Frye,
H Haller,
M Hausberg,
U C Hoppe, J Hoyer, [......],
T Keller,
B K Krämer,
R Kreutz,
S A Potthoff,
H Reinecke,
R Schmieder,
V Schwenger,
U Kintscher,
M Böhm,
L C Rump
[show abstract]
[hide abstract]
ABSTRACT: This commentary summarizes the expert consensus and recommendations of the working group 'Herz und Niere' of the German Society of Cardiology (DGK), the German Society of Nephrology (DGfN) and the German Hypertension League (DHL) on renal denervation for antihypertensive treatment. Renal denervation is a new, interventional approach to selectively denervate renal afferent and efferent sympathetic fibers. Renal denervation has been demonstrated to reduce office systolic and diastolic blood pressure in patients with resistant hypertension, defined as systolic office blood pressure ≥ 160 mm Hg and ≥ 150 mm Hg in patients with diabetes type 2, which should currently be used as blood pressure thresholds for undergoing the procedure. Exclusion of secondary hypertension causes and optimized antihypertensive drug treatment is mandatory in every patient with resistant hypertension. In order to exclude pseudoresistance, 24-hour blood pressure measurements should be performed. Preserved renal function was an inclusion criterion in the Symplicity studies, therefore, renal denervation should be only considered in patients with a glomerular filtration rate > 45 ml/min. Adequate centre qualification in both, treatment of hypertension and interventional expertise are essential to ensure correct patient selection and procedural safety. Long-term follow-up after renal denervation and participation in the German Renal Denervation (GREAT) Registry are recommended to assess safety and efficacy after renal denervation over time.
DMW - Deutsche Medizinische Wochenschrift 11/2011; 136(47):2418. · 0.53 Impact Factor
-
DMW - Deutsche Medizinische Wochenschrift 12/2010; 135(48):2399. · 0.53 Impact Factor
-
T Maier,
A Schwarting,
D Mauer,
R S Ross,
A Martens,
V Kliem,
J Wahl,
M Panning,
S Baumgarte,
T Müller, [......],
L Frisch,
N Pfeiffer,
H Fickenscher,
P Sauer,
C E Rupprecht,
M Roggendorf,
A Haverich,
P Galle, J Hoyer,
C Drosten
[show abstract]
[hide abstract]
ABSTRACT: This article describes multiple transmissions of rabies via transplanted solid organ from a single infected donor. The empirical Milwaukee treatment regimen was used in the recipients.
Symptomatic patients were treated by deep sedation (ketamine, midazolam, and phenobarbital), ribavirin, interferon, and active and passive vaccination. Viral loads and antibodies were continuously monitored.
Recipients of both cornea and liver transplants developed no symptoms. The recipient of the liver transplant had been vaccinated approximately 20 years before transplantation. Two recipients of kidney and lung transplants developed rabies and died within days of symptomatic disease. Another kidney recipient was treated 7 weeks before he died. The cerebrospinal fluid viral load remained at constant low levels (<10,000 copies/mL) for approximately 5 weeks; it increased suddenly by almost 5 orders of magnitude thereafter. After death, no virus was found in peripheral compartments (nerve tissue, heart, liver, or the small intestine) in this patient, in contrast to in patients in the same cohort who died early.
Our report includes, to our knowledge, the longest documented treatment course of symptomatic rabies and the first time that the virus concentration was measured over time and in different body compartments. The postmortem virus concentration in the periphery was low, but there was no evidence of a reduction of virus in the brain.
Clinical Infectious Diseases 03/2010; 50(8):1112-9. · 9.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A 22-year-old female without relevant underlying medical conditions presented with an acute onset of dysphasia. Her blood pressure was found to be 190/90 mm Hg.
Physical examination revealed left-sided hemiplegia and Broca's aphasia. A blood count showed anemia and thrombocytopenia. Cranial CT and MR imaging revealed small hypodense periventricular and cerebellar lesions. Mitral valve insufficiency and bilateral pleural effusion were found in echocardiography and chest x-ray, respectively.
A hypertensive emergency with cerebral and cardiac end-organ lesions was diagnosed. Blood pressure could not be controlled despite combination therapy of intravenous antihypertensive drugs. A full check-up for secondary hypertension revealed systemic lupus erythematosus (SLE) and catastrophic antiphospholipid syndrome (APS). Treatment of SLE/APS resulted in considerable improvement of blood pressure.
After ruling out frequent causes of hypertensive emergencies, such as insufficient adherence to drug therapy of primary hypertension, or secondary hypertension caused by renoparenchymal disease or renal artery stenosis, vasculitis or systemic diseases like SLE should be considered.
DMW - Deutsche Medizinische Wochenschrift 11/2009; 134(45):2274-7. · 0.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chronic renal failure does not only involve the risk for the patient of becoming dependent on hemodialysis, but also increases the risk of premature death due to cardiovascular events. In most renal diseases, progressive chronic loss of renal function develops once a critical extent of renal damage has occurred, independent of the course of the underlying renal disease. The key factors driving the progressive loss of renal function are, apart from the underlying nephrological disease, arterial hypertension and diabetes mellitus. The loss of renal function is also promoted by other factors, such as increased intake of dietary proteins, chronic inflammation, smoking, and anemia. With the help of a multimodal therapeutic concept, the progression of chronic renal failure can be delayed effectively. This approach comprises strict blood pressure control with a target blood pressure of 130/80 mmHg in patients with micro-albuminuria and of 120/75 mmHg in patients with proteinuria of >1 g/d. The preferred drugs for the treatment of hypertension are ACE inhibitors and angiotensin receptor blockers. In diabetics with renal insufficiency, target HbA1c levels below 7% are to be aimed for. Dietary protein intake should be restricted to 0.8-1 g/kg body weight/d. Additional therapeutic targets include nicotine abstinence, early treatment of renal anemia, weight reduction, and, if indicated, lipid-lowering therapy.
Der Urologe 07/2009; 48(7):793-803; quiz 804-5. · 0.50 Impact Factor
-
MMW Fortschritte der Medizin 01/2009; 150(51-52):47-8.
-
[show abstract]
[hide abstract]
ABSTRACT: Rabies is a fatal viral encephalitis characterized by a clinically acute and progressive course. With rare exceptions, there is a discrepancy between clinical outcome and frank histological alterations in rabies. Investigators have postulated that rabies virus may modify neurotransmission through occupancy of cellular receptors or alteration of ion channels. We took advantage of these observations to improvise a successful therapy for rabies. The Milwaukee protocol ( www.mcw.edu/rabies ) was further modified to treat two German patients. We measured pterins and monoamine neurotransmitter metabolites in the CSF of patients with rabies by HPLC with electrochemical or fluorescent detection. We report loss of tetrahydrobiopterin (BH(4)) and associated pathological decrease of dopaminergic and serotoninergic neurotransmission in three successive patients with rabies. CSF levels of BH(4) and neurotransmitter metabolites increased in two patients who were supplemented. Our findings support the long-standing speculation of modified neurotransmission in the pathogenesis of rabies, but by another mechanism. Brain turnover of dopamine and serotonin is reduced following rabies-acquired BH(4) deficiency. Neuronal nitric oxide synthase is BH(4)-dependent and may also be involved, possibly causing cerebrovascular insufficiency in one patient. This work must be carefully replicated in animal models and future patients. We are cautiously optimistic at the prospect of readily available, metabolically specific, enteral therapy for rabies.
Journal of Inherited Metabolic Disease 11/2008; 32(1):65-72. · 3.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chronic renal failure does not only involve the risk for the patient of becoming dependent on hemodialysis, but also increases the risk of premature death due to cardiovascular events. In most renal diseases, progressive chronic loss of renal function develops once a critical extent of renal damage has occurred, independent of the course of the underlying renal disease. The key factors driving the progressive loss of renal function are, apart from the underlying nephrological disease, arterial hypertension and diabetes mellitus. The loss of renal function is also promoted by other factors, such as increased intake of dietary proteins, chronic inflammation, smoking, and anemia. With the help of a multimodal therapeutic concept, the progression of chronic renal failure can be delayed effectively. This approach comprises strict blood pressure control with a target blood pressure of 130/80 mmHg in patients with micro-albuminuria and of 120/75 mmHg in patients with proteinuria of >1 g/d. The preferred drugs for the treatment of hypertension are ACE inhibitors and angiotensin receptor blockers. In diabetics with renal insufficiency, target HbA1c levels below 7% are to be aimed for. Dietary protein intake should be restricted to 0.8-1 g/kg body weight/d. Additional therapeutic targets include nicotine abstinence, early treatment of renal anemia, weight reduction, and, if indicated, lipid-lowering therapy.
Der Internist 04/2008; 49(4):451-61; quiz 462-3. · 0.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In the late eighties, several studies revealed the existence of a third vasodilating factor next to nitric oxide (NO) and prostacyclin (PGI2). As the action of this third factor is closely related to smooth muscle hyperpolarization, this factor was termed endothelium-derived hyperpolarizing factor (EDHF). The story of its investigation is a confusing one and several different candidate molecules and pathways have been proposed to account for the EDHF phenomenon. Major candidate molecules/mediators of EDHF signalling are K+, electrical coupling through gap junctions, cytochrome P450 metabolites, and endothelial small- and intermediate Ca2+-activated K+ channels (SK(Ca) and IK(Ca)). In this mini review, we wish to convey that EDHF is as powerful as NO and PGI2 in terms of blood pressure regulation and that deficiency in EDHF signalling contribute to several cardiovascular pathologies such as hypertension, chronic renal failure, and diabetes. In addition, we focus on recent insight into the EDHF phenomenon provided by novel genetic animal models, such as mice deficient of either endothelial SK(Ca) or IK(Ca) and the impact of channel deficiency on endothelial function, EDHF signalling, and arterial blood pressure.
Kidney International 08/2007; 72(2):145-50. · 6.61 Impact Factor
-
DMW - Deutsche Medizinische Wochenschrift 12/2006; 131(46):2601-4. · 0.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Endothelial cation channel are important regulators of vascular tone by modulating intracellular Ca(2+)-signaling and thus adequate synthesis of vasodilating factors. The overall importance of these ion channels suggests that they may represent novel pharmacotherapeutic targets in addition to the well-known voltage-gated calcium channels in vascular smooth muscle. In this short overview we summarize the current knowledge about endothelial ion channels and their roles for endothelium-dependent vasodilatation. Furthermore, we perspectively discuss the usefulness of specific openers of endothelial Ca(2+)-activated K(+)-channels and TRPV-channels as novel antihypertensive drugs.
DMW - Deutsche Medizinische Wochenschrift 12/2005; 130(46):2637-9. · 0.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dent's disease is an inherited tubulopathy caused by a mutation in the CLCN5 chloride channel gene. It is characterized by low-molecular weight proteinuria, hypercalciuria, nephrolithiasis or nephrocalcinosis, rickets and eventual-progressive renal failure. Onset of clinical symptoms show a great variability, making a diagnosis at an early stage of the disease often difficult. Given the variably clinical picture, genetic analysis can provide a reliable method to confirm the diagnosis. Here, we report on the case of a patient with progressive renal failure showing signs of a tubular lesion and symptoms of Dent's disease. Although this rare disease was suspected by means of the clinical features, it was genetic analysis that confirmed the diagnosis and revealed a novel mutation in the CLCN5 gene.
Clinical nephrology 12/2004; 62(5):387-90. · 1.17 Impact Factor
-
DMW - Deutsche Medizinische Wochenschrift 12/2002; 127(45):2392-5. · 0.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mechanosensitive ion channels have been suggested to act as endothelial mechanosensors for hemodynamic forces. The present study tested the hypothesis that the pressure-activated cation channel (PAC), a novel type of endothelial mechanosensitive ion channel, is involved in salt sensitivity in the Sabra rat model of hypertension. Groups of Sabra salt-sensitive (SBH/y) and salt-resistant (SBN/y) rats were loaded with deoxycorticosterone-acetate (DOCA)-salt for 8 wk or were fed a regular diet. Single channel function of PAC in SBH/y and SBN/y rats was investigated in intact endothelium of mesenteric artery using the patch-clamp technique. After DOCA-salt treatment, the SBH/y rats showed a full hypertensive response, whereas SBN/y rats were normotensive. Rats of both strains that received a regular diet were normotensive. In endothelium of both Sabra rats, Ca(2+) permeable PAC that was activated by positive pipette pressures was identified. Apparent PAC density (percentage of patches with PAC activity) was reduced in hypertensive SBH/y rats that were loaded with DOCA-salt compared with salt-loaded normotensive SBN/y rats (6 +/- 2% versus 24 +/- 8%, respectively; P < 0.05). In normotensive SBH/y and SBN/y rats that received a regular diet, PAC density was not altered. Mechanosensitivity and unitary conductance of endothelial PAC were similar in both strains under a regular diet as well as salt loading with DOCA-salt. In conclusion, the decreased density of PAC in mesenteric endothelium from hypertensive SBH/y rats indicates an impaired ion channel regulation. The defective PAC function presumably leads to an impaired mechanosensitive Ca(2+) entry and might contribute to endothelial dysfunction and high BP in this type of salt-sensitive genetic hypertension.
Journal of the American Society of Nephrology 09/2001; 12(8):1624-9. · 9.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The pressure-activated cation channel (PAC), a novel type of mechanosensitive channel, has been suggested to act as a mechanosensor in aortic endothelium. In experimental hypertension, PAC function was up-regulated in the established phase of high blood pressure. This association of altered PAC function and elevated arterial pressure suggests that PAC function is regulated by alterations in blood pressure. In the present study, we electrophysiologically investigated PAC function in intact endothelium of aorta (EA) and mesenteric artery (EMA) from stroke-prone spontaneously hypertensive rats (SHRSP), SHRSP after 4 weeks of treatment with quinaprilat (10 mg/kg/day), and normotensive Wistar-Kyoto (WKY) rats. In untreated SHRSP and WKY rats, systolic blood pressure (SBP) was 201+/-3 mm Hg and 142+/-3 mm Hg, respectively. In quinaprilat-treated SHRSP, SBP was lowered to 135+/-5 mm Hg. Apparent PAC density (percentage of patches with PAC activity) in EA of untreated SHRSP (63.7%+/-7.3%) was 2.4-fold higher than in WKY rats (26.0%+/-5.0%). In contrast, no significant PAC up-regulation was detected in EMA of SHRSP (15.7%+/-4.2%) compared with WKY rats (12.0%+/-3.9%). In EA of quinaprilat-treated normotensive SHRSP, PAC density (27.1%+/-5.2%) was lowered to levels found in normotensive WKY rats. Unitary conductance and pressure sensitivity of PAC were not altered in either hypertensive or normotensive rats. Taken together, hypertension-induced increases of endothelial PAC density can be completely reversed by antihypertensive therapy. The PAC up-regulation in EA was interpreted as a compensatory mechanism to enhance Ca2+-influx and subsequently the synthesis of vasodilatory factors. This mechanism is missing in EMA of SHRSP, which might contribute to high blood pressure in this rat model of severe genetic hypertension.
American Journal of Hypertension 08/2001; 14(7 Pt 1):716-21. · 3.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ca(2+)-activated K(+) (K(Ca)) channels control endothelial Ca(2+) homeostasis and the formation of vasodilators. After angioplasty, dysfunction of the regenerated endothelium leads to abnormal vasoregulation. In this study, we tested the expression and function of K(Ca) channels in regenerated endothelium at 6 weeks after balloon catheter injury of rat carotid arteries (CAs) by using single-cell reverse transcription-polymerase chain reaction, patch-clamp techniques, and analysis of vasoreactivity. In single regenerated endothelial cells (ECs), the percentage of ECs expressing the K(Ca) genes, rSK3 (12+/-8%) and rIK1 (22+/-9%), was significantly lower compared with the percentage of native ECs expressing these genes (rSK3 58+/-8%, rIK1 64+/-10%). In patch-clamp experiments, K(Ca) currents and acetylcholine-induced hyperpolarization were markedly reduced in regenerated ECs (shift of membrane potential -6+/-3 mV) compared with those in native ECs (shift of membrane potential -21+/-5 mV). In pressure myograph experiments, acetylcholine-induced dilation was impaired in reendothelialized CAs compared with normal CAs. Intraluminal application of the K(Ca) blocker apamin and charybdotoxin inhibited dilation by 30% in normal CAs but was without effect in reendothelialized CAs. Intraluminal application of 1-ethyl-2-benzimidazolinone (100 micromol/L), an opener of K(Ca) channels, evoked dilation by 29% in normal CAs but had no effect in reendothelialized CAs. In conclusion, the impaired expression of K(Ca) channels in regenerated endothelium results in defective hyperpolarization and impaired dilation. Thus, the impaired K(Ca) channel function contributes to functional alterations of regenerated endothelium after angioplasty.
Circulation Research 08/2001; 89(2):174-9. · 9.49 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ca(2+) mobilization plays an important role in endothelial function by stimulating Ca(2+)-dependent synthesis of vasodilating factors. In addition to inositol-1,4,5-trisphosphate (InsP(3)) mediated Ca(2+) mobilization, Ca(2+) release from ryanodine-sensitive pools and Ca(2+)-influx through TRP channels have been suggested to be important in endothelial Ca(2+)-signaling. However, the function and molecular identity of TRP channels and ryanodine receptors in human endothelium in situ are still elusive. We hypothesized that expression of ryanodine-receptors (RyR) and TRP channels differs between human endothelium in situ and in cultured cells.
By combining single-cell RT-PCR and patch-clamp techniques, expression of RyR and TRP channels was determined in situ in endothelial cells of human mesenteric artery (HMAECs) obtained from patients undergoing bowel resection and in the endothelial cell line EA.hy926.
At the single cell level, expression of RyR 3 was detected in 25 and 5% of HMAECs and EA.hy926 samples, respectively. Expression of the RyR 1 and 2 was not detected in either HMAECs or EA.hy926. In patch-clamp experiments in HMAECs, applications of caffeine (0.5 mM) induced sustained hyperpolarization mediated by activation of Ca(2+)-activated K channels. In EA.hy926, caffeine-induced hyperpolarization was not detected. Single HMAECs expressed the TRP genes, TRP1 and TRP3, but not TRP 4 and 6. The TRP1 was the predominantly expressed TRP gene in HMAECs in situ whereas TRP3 expression was rarely detected. EA.hy926 expressed only TRP1. In patch clamp experiments in HMAECs, Ca(2+)-store depletion activated non-selective cation currents leading to Ca(2+) entry.
Our findings suggest that, in addition to InsP(3) mediated Ca(2+) release, Ca(2+) release from ryanodine-sensitive stores mediated by RyR3 and Ca(2+) entry through TRP1 might represent important components of endothelial Ca(2+) signaling in situ and thereby of endothelial function in intact human blood vessels.
Cardiovascular Research 08/2001; 51(1):160-8. · 6.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ca(2+)-activated K(+) (K(Ca)) channels have been suggested to play a role in the control of endothelial functions such as regulation of vascular tone and cell proliferation. We established a method for single-cell reverse transcriptase-polymerase chain reaction analysis in combination with the patch-clamp technique to characterize K(Ca) channel expression and function in single endothelial cells (ECs) within the endothelial monolayer of intact human mesenteric arteries (MAs) and in disease states. We tested whether endothelial K(Ca) channel expression and function are altered in MAs obtained from patients with colonic adenocarcinoma (CA) compared with those in MAs from non-cancer patients with inactive diverticulitis. Expression of the intermediate-conductance K(Ca) channel (hIK1) was detected in non-cancer and CA patients. In whole-cell patch-clamp measurements, only ECs expressing hIK1 exhibited corresponding K(Ca) currents, whereas respective K(Ca) currents were missing in hIK1-negative ECs. This heterogeneity of hIK1 expression patterns is indicative of a specialized subset of ECs within the endothelial monolayer. In CA patients, compared with non-cancer patients, a 2.5-fold increase in hIK1-expressing ECs per MA was observed (P:<0.05). However, K(Ca) current densities in hIK1-expressing ECs of both groups were similar. In addition to hIK1, expression of the large-conductance K(Ca) channel (hSlo) was detected in single ECs from CA patients. The increased K(Ca) channel expression in CA patients resulted in a 2. 7-fold increase of bradykinin-induced endothelial hyperpolarization compared with controls (P:<0.05). This increased expression and function of K(Ca) channels might indicate an altered functional state of the endothelium in cancer patients and could play a role in tumor angiogenesis.
Circulation Research 09/2000; 87(6):496-503. · 9.49 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hyperpolarizing large-conductance, Ca(2+)-activated K(+) channels (BK) are important modulators of vascular smooth muscle and endothelial cell function. In vascular smooth muscle cells, BK are composed of pore-forming alpha subunits and modulatory beta subunits. However, expression, composition, and function of BK subunits in endothelium have not been studied so far. In patch-clamp experiments we identified BK (283 pS) in intact endothelium of porcine aortic tissue slices. The BK opener DHS-I (0.05-0.3 micromol/l), stimulating BK activity only in the presence of beta subunits, had no effect on BK in endothelium whereas the alpha subunit selective BK opener NS1619 (20 micromol/l) markedly increased channel activity. Correspondingly, mRNA expression of the beta subunit was undetectable in endothelium, whereas alpha subunit expression was demonstrated. To investigate the functional role of beta subunits, we transfected the beta subunit into a human endothelial cell line (EA.hy 926). beta subunit expression resulted in an increased Ca(2+) sensitivity of BK activity: the potential of half-maximal activation (V(1/2)) shifted from 73.4 mV to 49.6 mV at 1 micromol/l [Ca(2+)](i) and an decrease of the EC(50) value for [Ca(2+)](i) by 1 microM at +60 mV was observed. This study demonstrates that BK channels in endothelium are composed of alpha subunits without association to beta subunits. The lack of the beta subunit indicates a substantially different channel regulation in endothelial cells compared to vascular smooth muscle cells.
The FASEB Journal 06/2000; 14(7):885-94. · 5.71 Impact Factor
