Search

ZUSAMMENFASSUNGDie gemeinnützige Stiftung Patienten-Heimversorgung (PHV) ist seit ihrer Gründung im Jahr 1973 in der Dialyseversorgung engagiert und im deutschen Dialysemarkt fest etabliert. Sie zählt – neben dem KfH Kuratorium für Dialyse und Nierentransplantation e. V. – zu den führenden gemeinnützigen Dialyseanbietern in Deutschland. Die PHV versteht sich als Partner, insbesondere auch von niedergelassenen nephrologischen Facharztpraxen, und erbringt die für die Dialysebehandlung erforderlichen Sach- und Dienstleistungen, einschließlich des Personaleinsatzes in der Pflege. Die Digitalisierung sieht die Stiftung als große Chance. Ziel der PHV ist es, mithilfe digitaler Prozesse die administrativen Tätigkeiten und Abläufe in ihren Dialysezentren so effizient wie möglich zu gestalten, um ihre Pflegekräfte in diesem Bereich zu entlasten.

Die arterielle Hypertonie gehort in den westlichen Industrienationen durch ihre hohe Pravalenz zu den haufigsten chronischen Erkrankungen und ist ein Hauptrisikofaktor fur kardiovaskulare Morbiditat und Mortalitat. In der Pathophysiologie der unkontrollierten Hypertonie kommt der Uberaktivitat des sympathischen Nervensystems eine wichtige Bedeutung zu. Seit einigen Jahren steht mit der renalen Denervation (RDN) ein katheterbasiertes Verfahren zur selektiven renalen Sympathektomie zur Verfugung. In mehreren randomisierten, durch Scheinprozedur kontrollierten Studien konnte die Wirksamkeit und Sicherheit des Verfahrens bestatigt werden, sodass davon auszugehen ist, dass die RDN auch klinisch zum Einsatz kommen wird. Ziel der Zertifizierung der Renalen-Denervations-Zentren ist es, einen national verbindlichen Mindeststandard fur Zentren zur Durchfuhrung der RDN zu definieren sowie uber eine Netzwerkbildung die Betreuung der Patienten mit unkontrollierter Hypertonie zu optimieren. Institutionen, welche die RDN durchfuhren, wird im Zuge eines Evaluationsverfahrens die Moglichkeit gegeben, entsprechend zertifiziert zu werden.

Kidney patients age faster and vascular risk factors intensify the process. Lifetime is reduced up to 16 years in patients with diabetes mellitus type 2 and kidney disease. SGLT2 inhibitors play a significant role in maintaining organ function. By inhibiting the SGLT2 transporter in the proximal tubule of the kidneys, energy and water are continuously excreted and metabolic processes that are counter-regulated are set in motion. This hypometabolic adaptation supports organ functions and induces longevity. Kidney protection extends life expectancy of patients with diabetes mellitus type 2.Also patients with heart failure benefit and a 3-stage therapy is newly being discussed. The beta blocker is combined with an SGLT2 inhibitor in the first stage. In the second stage, the angiotensin receptor/neprilysin inhibitor and then a mineralocorticoid receptor antagonist (MRA) is used. These therapies have a complementary effect.

Kidney patients age faster and vascular risk factors intensify the process. Lifetime is reduced up to 16 years in patients with diabetes mellitus type 2 and kidney disease. SGLT2 inhibitors play a significant role in maintaining organ function. By inhibiting the SGLT2 transporter in the proximal tubule of the kidneys, energy and water are continuously excreted and metabolic processes that are counter-regulated are set in motion. This hypometabolic adaptation supports organ functions and induces longevity. Kidney protection extends life expectancy of patients with diabetes mellitus type 2.Also patients with heart failure benefit and a 3-stage therapy is newly being discussed. The beta blocker is combined with an SGLT2 inhibitor in the first stage. In the second stage, the angiotensin receptor/neprilysin inhibitor and then a mineralocorticoid receptor antagonist (MRA) is used. These therapies have a complementary effect.

"Choosing Wisely" is an initiative of the German Society of Internal Medicine with the aim to provide recommendations for diagnostic and therapeutic procedures that are of clear medical and scientifically proven benefit, but are rather underused in daily practice. As such, these positive recommendations are indicative of an undersupply. On the other hand, the German Society of Internal Medicine also developed "negative recommendations", pointing out diagnostic and therapeutic procedures that are frequently used but for which there is little or no scientific evidence. They indicate oversupply. So far, the various internal medicine societies have each developed five positive and five negative recommendations, and there are more to come.

In renal replacement therapy, different methods are available: hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KTx). In addition, variants can be used: HD as a home HD or center HD, PD as a conventional PD or automated (cycler) PD, KTx as a potentially short-term predictable living donation or conventional donor kidney donation. The patient and his familiar or caring environment must be informed accordingly. This means first of all: information about which procedures of kidney replacement therapy are possible and can be offered. Then the specific risks associated with each procedure should be elucidated (e. g. HD and shunt bleeding, PD and peritonitis, KTx and infections/neoplasias). This necessarily includes a structured documentation of the educating center/doctor about the communicated information and decisions taken.

Background Although citrate dialysate (CiDi) is regarded to be safe, dialysis modalities using higher dialysate volumes, like haemodiafiltration (HDF), may expose patients to higher citrate load and thus increase the risk of complications. We investigated the residual risk of CiDi compared with standard dialysate (StDi) in patients on different dialysis modalities and its effect on dialysis dose. Methods In a multicentre randomized crossover study, 92 dialysis patients (HDF post-dilution: n = 44, HDF pre-dilution: n = 26, haemodialysis: n = 25) were treated for 4 weeks with each dialysate (StDi and CiDi). Hypocalcaemia (ionized calcium ≤0.9 mmol/L), alkalosis (pH ≥7.55), post-treatment bicarbonate ≥32 mmol/L, pre-treatment bicarbonate ≥27 mmol/L, intra-dialytic events (IEs) and adverse events (AEs) between dialysis sessions were investigated as primary end points. The secondary objective was dialysis efficacy, i.e. dose and removal ratios of urea, creatinine, phosphate and β-2-microglobulin. Results Post-dialysis overcorrection of bicarbonate (>32 mmol/L) was less frequent with CiDi (P = 0.008). Other predefined calcium and acid-base disturbances did not vary. There was no significant difference in IE. However, more patients developed AEs such as fatigue, muscle spasms or pain using CiDi (StDi: 41 versus CiDi: 55 patients, P = 0.02), particularly in the first 2 weeks of exposure. Dialysis efficacy was comparable with both dialysates. Conclusions It can be confirmed that CiDi is not associated with the development of severe calcium and acid-base disorders, even when dialysis modalities with higher citrate loads are used. However, a refinement of the CiDi composition to minimize AEs is necessary.

Nephrologische Krankenhausabteilungen sind in erster Linie fur die Versorgung stationarer nierenkranker Patienten zustandig. Die Versorgung umfasst diagnostische Masnahmen und Therapieleistungen inklusive Nierenersatztherapie. D. h., obwohl Nierenersatztherapie in Deutschland uberwiegend ambulant durchgefuhrt wird, mussen auch nephrologische Krankenhausabteilungen die Strukturen fur eine 24-Stunden-/7-Tage-Versorgung, inklusive Dialysetherapie, vorhalten konnen. Nephrologische Krankenhausabteilungen sind auserdem die wichtigste Ausbildungsstatte fur den arztlichen nephrologischen Nachwuchs, dem wahrend der Weiterbildungszeit das gesamte Spektrum diagnostischer und therapeutischer Leistungen angeboten werden sollte. Da die meisten nephrologischen Krankenhausabteilungen in Deutschland bis dato nicht uber eine eigene Ermachtigung zur Behandlung ambulanter Dialysepatienten verfugen, sind Kooperationsmodelle mit dem ambulanten Bereich die Antwort auf die Frage, wie das gesamte nephrologische Spektrum in Krankenhausabteilungen abgebildet werden kann. Diese Ubersicht wird die verschiedenen, in Deutschland derzeit praktizierten Kooperationsmodelle kurz beschreiben. Ein weiterer wichtiger Aspekt fur die Attraktivitat einer nephrologischen Krankenhausabteilung im Hinblick auf die Ausbildungsqualitat und Wirtschaftlichkeit ist die Kooperation mit anderen Fachabteilungen. Dies wird an konkreten Beispielen – Zusammenarbeit mit der Kardiologie und anderen Fachabteilungen – beschrieben.

"Choosing Wisely" is an initiative of the German Society of Internal Medicine with the aim to provide recommendations for diagnostic and therapeutic procedures that are of clear medical and scientifically proven benefit, but are rather underused in daily practice. As such, these positive recommendations are indicative of an undersupply. On the other hand, the German Society of Internal Medicine also developed "negative recommendations", pointing out diagnostic and therapeutic procedures that are frequently used but for which there is little or no scientific evidence. They indicate oversupply. So far, the various internal medicine societies have each developed five positive and five negative recommendations, and there are more to come.

Background: Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce. Methods: In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). Results: A total of 24 patients were analyzed, 23 with relapsing–remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7–10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments. Conclusions: Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.

Ein wichtiger Kofaktor fur die Anamie chronisch Nierenkranker ist der Eisenmangel. In der Behandlung der renalen Anamie ist die Berucksichtigung ausreichender Eisenspeicher in den letzten Jahren deutlich in den Vordergrund geruckt. Die kurzlich veroffentlichten Leitlinien der internationalen KDIGO-Initiative haben die Zielwerte fur relevante Messparameter des Eisenstoffwechsels wie Transferrinsattigung und Ferritin nach oben verschoben, wahrend die Zielwerte fur den Serum-Hamoglobin-Wert nach unten korrigiert wurden. Diese Veranderungen beziehen sich sowohl auf Pradialyse- wie auf Dialysepatienten. Zur Eisensubstitution stehen orale wie intravenos zu verabreichende Substanzen zur Verfugung. Da die enterale Eisenresorptionskapazitat niedrig ist, wird eine orale Substitution meist nur zum Erhalt ausreichender Eisenspeicher im Pradialysebereich reichen konnen, nicht aber zum Auffullen entleerter Speicher. Hierzu wird in der Regel eine intravenose Eisengabe notwendig sein. Die verschiedenen zur Verfugung stehenden Eisenpraparate unterscheiden sich in ihrer Zusammensetzung, Vertraglichkeit und in der maximal pro Einzelverabreichung moglichen Hochstdosis. Ein orientierender Vergleich soll hier dargestellt werden.

Background: A marked proportion of multiple sclerosis (MS) relapses is followed by incomplete recovery. Our aim was to considerably increase the evidence of the clinical use of immunoadsorption (IA) as escalation therapy for patients with MS relapse. Methods: A retrospective multicenter study was performed in MS patients with steroid refractory relapse who were treated with tryptophan IA. The main outcome parameter was change of acute relapse-related disability assessed by Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). IA treatments were performed using single-use tryptophan adsorbers. Results: Data of 147 MS patients and 786 single IA treatments were analyzed. Treatment with IA was commenced in mean 32 ± 35 days after the onset of relapse. One hundred and five out of 147 patients (71.4%) improved functionally after mean 5.4 IA treatments within 7-10 days. EDSS improved from median 5 (interquartile range, IQR 3.5) to 4 (IQR 2.5) (p < 0.001). In patients with ON (n = 32), VA improved after the IA series in 84% of cases from median 0.2 (IQR 0.6) to 0.6 (IQR 0.66) (p < 0.001). In 98.9% of IA treatments, no clinically relevant side effect was reported. Conclusion: Tryptophan IA was found to be effective and well tolerated as escalation therapy for MS relapse.

Objective: To evaluate once-monthly continuous erythropoiesis receptor activator (C.E.R.A.) in patients with chronic kidney disease (CKD) for two years under standard conditions. Methods: In a non-interventional study, C.E.R.A. was administered according to local practice in patients with dialysis dependent or non-dialysis dependent CKD. Results: 206 patients were evaluable to month 24. In the dialysis dependent and non-dialysis dependent patients who had received ESA therapy prior to study entry, Hb remained stable from baseline to the end of the study: mean (SD) change was -0.3 (1.5) g/dL (n=148) and 0.3 (1.6) g/dL (n=33), respectively. The mean (SD) dose of C.E.R.A. was 114 (78) μg in dialysis dependent patients and 97 (71) μg in non-dialysis dependent patients at baseline, remaining virtually unchanged during the study (109 (76) μg and 99 (68) μg). During the two-year study, dialysis dependent and non-dialysis dependent patients received a mean of 6.1 and 4.3 dose changes, respectively. Discontinuation due to adverse events was rare (2.9%). Conclusions: Once-monthly C.E.R.A. is effective and convenient in dialysis dependent and non-dialysis dependent patients with renal anemia under routine conditions for at least two years, and requires few dose changes. C.E.R.A. was well-tolerated with a good safety profile over the two-year study period.

The microtubule associated tumor suppressor gene 1 (MTUS1) is a recently published tumor suppressor gene, which has also been shown to act as an early component in the growth inhibitory signaling cascade of the angiotensin II type 2 receptor (AT2R). In this study we report the generation of MTUS1 knock-out (KO) mice, which develop normally but reveal higher body weights and slightly decreased blood pressure levels. Twenty-eight percent of the studied MTUS1 KO mice also developed heart hypertrophy and 12% developed nephritis, independent of blood pressure levels. Forty-three percent of the MTUS1 KO mice revealed lymphoid hyperplasia affecting spleen (20%), kidney (37%), lung (23%), lymph nodes (17%), and liver (17%) accompanied with leukocytosis, lymphocytosis, and mild anemia. One animal (3%) developed a marginal zone B-cell lymphoma affecting submandibular salivary gland and regional lymph nodes. The symptoms of all mentioned animals are consistent with a B-cell lymphoproliferative disease with features of systemic lupus erythematosus. In addition, body weight of the MTUS1 KO mice was significantly increased and isolated skin fibroblasts showed increased cell proliferation and decreased cell size, compared to wild-type (WT) fibroblasts in response to depleted FCS concentration and lack of growth factors. In conclusion we herein report the first generation of a MTUS1 KO mouse, developing spontaneous heart hypertrophy and increased cell proliferation, confirming once more the anti-proliferative effect of MTUS1, and a SLE-like lymphoproliferative disease suggesting crucial role in regulation of inflammation. These MTUS1 KO mice can therefore serve as a model for further investigations in cardiovascular disease, autoimmune disease and carcinogenesis.

Anemia is a well-recognized feature in patients with chronic kidney disease (CKD). Recently, two large-scale trials, CREATE and CHOIR, pointed to the complexity of maintaining stable hemoglobin (Hb) levels over time. According to these data, patients failing to achieve the target range of Hb levels between 11–12 g/dL may be at increased risk of dying. Both low and high Hb levels are associated with increased cardiovascular events and death. One reason for failure to achieve stable Hb levels within the target range is Hb cycling. Several causes may be responsible for a cyclic pattern of Hb levels: drug-related factors such as differences in pharmacokinetics and bioavailability in erythropoiesis-stimulating agents (ESAs) as well as difficulties in iron supplementation may induce Hb instability in patients with CKD. Similarly, patient-related factors such as an inflammatory status or protein energy wasting are associated with this phenomenon. Further, variations in fluid balance and bio-compatibility of dialyzer membranes, by differentially affecting inflammation, render the hemodialysis treatment itself a risk factor for Hb cycling. Strategies to reduce Hb cycling are necessary to obtain improved clinical out-comes. This review will describe the phenomenon of Hb cycling, highlighting potential contributing factors and discussing the possible clinical conditions.

Background: C-reactive protein (CRP) is a risk marker for cardiovascular disease and has been implicated in atherogenesis. In atherosclerotic plaques, it colocalizes with oxidized LDL (oxLDL) and promotes oxLDL uptake by macrophages, suggesting an important cross-talk between CRP and lipid processing. A growing body of evidence indicates the existence of distinct configurations of human CRP, native pentameric (nCRP) and structurally modified monomeric (mCRP), that elicit opposing bioactivities in vitro and in vivo. Here, we tested the impact of mCRP and nCRP on the uptake of acetylated LDL (acLDL), which is internalized by receptors similar to those of oxLDL in human endothelial cells.Methods: We cultured human umbilical vein endothelial cells (HUVECs) for 8 h with mCRP or nCRP (10–100 mg/L) and measured the uptake of acLDL (10–100 mg/L) over a 20-h period by FACS analysis. To assess the receptors involved, we used function-blocking antibodies against Fc γ receptor CD16 (FcγRIII) and CD32 (FcγRII), and RT-PCR analysis of CD16, CD32, and the receptor for oxidized LDL (LOX-1). Uptake of acLDL and CRP isoforms was visualized by immunofluorescence.Results: Culture of HUVECs with mCRP, but not nCRP, decreased uptake of acLDL, which was not prevented by anti-CD16 or anti-CD32 antibodies. LOX-1, CD16, and CD32 were undetectable by RT-PCR. Immunofluorescence showed decreased cytoplasmic acLDL staining in human umbilical vein endothelial cells (HUVECs) treated with mCRP, but not with nCRP.Conclusions: Monomeric CRP, but not nCRP, decreased acLDL uptake in human endothelial cells independent of CD16, CD32, or LOX-1. Our data support a protective role of mCRP in cardiovascular disease.

Objective: In addition to being a risk marker for cardiovascular disease, recent data suggests that C-reactive protein (CRP) induces endothelial dysfunction and promotes oxidative stress. We evaluated the effects of two conformers of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) on vessel function and production of reactive oxygen species (ROS) in an in-vivo model of atherosclerosis. Methods and Results: Female ApoE −/− mice, fed a “western-type” diet, were treated with either human nCRP or mCRP (2.5 mg/kg s.c., weekly) or saline for 8 weeks. Endothelium-dependent and endothelium-independent vascular functions were assessed in isolated aortic rings under isometric conditions. Production of ROS in aortic rings was measured by electron spin resonance (ESR). Endothelium-dependent relaxation was impaired in nCRP-treated but not in mCRP-treated ApoE −/− mice. This impairment was reversed by preincubation with an inhibitor of inducible nitric oxide synthase (iNOS). Endothelium-independent relaxation, and iNOS and endothelial NOS (eNOS) protein expressions were similar among all groups. ESR experiments revealed lesser amounts of superoxide in the nCRP group as compared to the saline group, which is consistent with an increased transformation of NO to peroxynitrite. Conclusions: nCRP can facilitate cardiovascular disease through impairment of endothelium-dependent vasoreactivity, in a manner that involves increased iNOS activity and a potential for increased peroxynitrite formation. © 2007 Elsevier Ireland Ltd. All rights reserved.

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17β-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17β-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17β-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17β-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.

Oxidized LDL (OxLDL) is a proatherogenic lipoprotein, accumulating in the vascular wall and contributing to the pathogenesis of vascular dysfunction early in the development of atherosclerosis. Enhanced serum levels of OxLDL, as well as antibodies against its epitopes, are predictive for endothelial dysfunction and coronary heart disease. While enhanced oxidative stress is one factor triggering formation of OxLDL, OxLDL itself has been identified as a potent stimulus for vascular oxygen radical formation, causing a vicious circle. OxLDL-induced O(2)(-) formation, largely through activation of NADPH oxidase, but also through uncoupling of endothelial NO-synthase and through direct O(2)(-) release, leads to endothelial dysfunction. Furthermore, OxLDL-induced O(2)(-) formation has a strong impact on tissue remodeling, resulting in either cell growth - proliferation or hyperplasia - or apoptotic cell death. The effect of OxLDL on cell cycle regulation is mediated by activation of the small GTPase RhoA and consequent regulation of p27(KIP1), a key enzyme of the cell cycle. In addition, OxLDL-induced activation of RhoA sensitizes the contractile apparatus of the vessel wall, enhancing the contractile tonus and favoring vasospasm. Thus, through a variety of mechanisms, OxLDL importantly contributes to vascular dysfunction and remodeling.

Background:L-Arginine (L-Arg), a substrate of nitric oxide synthases, improves renal function in ischemic acute renal failure (iARF). We evaluated whether L-Arg improves renal morphology and cell survival in the course of iARF. Methods and Results: iARF was induced in rats by bilateral clamping of renal arteries for 45 min. L-Arg was applied intraperitoneally during clamping, and orally during 14 days of follow-up. Morphology and cell survival of renal cortical and medullar tissue was analyzed on days 1, 3, 7, and 14 of follow-up, using toluidine blue staining and immunohistochemistry of perfusion-fixated tissue, and Western blot analysis of tissue homogenate. Renal tubular injury showed typical features of necrosis and was most severe on days 1 and 3 after clamping, predominantly in S3 segments, with almost complete recovery by day 14. Enhanced medullar monocyte infiltration, determined by ED-1 expression as well as by immunohistochemistry, and enhanced expression of proliferating cell nuclear antigen (PCNA), indicative of proliferation and regeneration, accompanied these morphological changes. Compared to controls, L-Arg had no impact on renal morphology, ED-1, and PCNA expression. Furthermore, expression of markers of apoptosis Bcl-2, Bax, and cleaved caspase-3 was only slightly increased in iARF rats, compared to sham-operated animals, and was also not influenced by L-Arg. Conclusion: Despite its repeatedly reported positive impact on renal function as also shown in our model, L-Arg does not alter cell death and proliferation in the course of iARF in our model. Thus, different mechanisms have to be considered, in particular improved intrarenal hemodynamics.

Background—C-reactive protein (CRP) may have proatherogenic but also vasoprotective properties. We tested the hypothesis that the configuration of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) determines these different characteristics in an in vivo model.Methods and Results—We investigated the effects of human nCRP and mCRP on the development of atherosclerosis in apolipoprotein E–knockout (ApoE−/−) mice. Treatment with nCRP for 8 weeks (2.5 mg/kg SC weekly) resulted in a 4-fold-higher mean aortic plaque area in 14-week-old female ApoE−/−mice compared with the saline controls. In contrast, mean plaque size was decreased by ≈50% in mCRP-treated ApoE−/−mice (2.5 mg/kg SC weekly). Using immunohistochemistry, we report the natural presence of the mCRP antigen in saline controls. mCRP antigen was expressed in smooth muscle cells and extracellularly in the vicinity of the plaques to a similar level in both CRP-treated groups and saline controls. mCRP and ApoB colocalized with macrophages and were equally upregulated in all aortic plaques. Vascular cell adhesion molecule expression was increased, and CD154 and intercellular adhesion molecule showed a trend for higher expression in nCRP-treated compared with mCRP-treated mice. CD154 expression in the vessel wall and plaque size correlated significantly. mCRP-treated ApoE−/−exhibited higher serum levels of the antiinflammatory interleukin-10 compared with the other 2 groups.Conclusions—Here, we show that mCRP and nCRP have opposite effects on atherosclerosis in ApoE−/−mice. These data may explain in part the conflicting activities previously reported for CRP in models of atherogenesis.

Den meisten kardiovaskularen Erkrankungen liegt ein arteriosklerotischer Umbau des Gefassystems zugrunde. In jungerer Zeit wurden die Bedeutung inflammatorischer Prozesse fur die Entwicklung der Arteriosklerose und deren Folgekrankheiten erkannt und die Arteriosklerose als chronische Entzundung identifiziert. Im fruhen, makroskopisch nicht identifizierbaren Stadium der Endotheldysfunktion stehen erhohte Endothelpermeabilitat, Expression von Adhasionsmolekulen sowie Anheftung und Immigration von Leukozyten im Vordergrund. Die Induktion von oxidativem Stress, u. a. durch Stimulation der vaskularen NAD(P)H-Oxidase, scheint dabei eine zentrale Rolle zu spielen. Wiewohl die experimentelle Datenlage zur inflammatorischen Genese der Arteriosklerose schlussig ist, sind die sich daraus ergebenden therapeutischen Konsequenzen weniger klar. Prospektive Studien mit Antibiotika oder Antioxidanzien fielen bislang eher enttauschend aus. Allerdings gibt es gute Evidenz dafur, dass ein Teil der Effekte der bei kardiovaskularen Erkrankungen etablierten Medikamente, wie der Statine und der Hemmer des Renin-Angiotensin-Aldosteron-Systems, uber eine antiinflammatorische und antioxidative Wirkung zustande kommt. Zur Thematik der Antioxidanzien bleibt festzuhalten, dass neue Studien mit besserem Design und/oder adaquater statistischer Power abgewartet werden mussen.

Vasopeptidase inhibition: A new treatment approach for endothelial dysfunction. Angiotensin-converting enzyme (ACE) inhibition is a well-established principle in the treatment of endothelial dysfunction. Numerous preclinical and clinical studies have clearly demonstrated the beneficial effects of inhibiting the renin-angiotensin-aldosterone system (RAS) in states of impaired endothelial function. The successful use of ACE inhibitors encouraged attempts to inhibit other key enzymes in the regulation of vascular tone, such as the neutral endopeptidase (NEP). Similar to ACE, NEP is an endothelial cell surface metalloproteinase that is involved in the degradation of several regulatory peptides, including the natriuretic peptides, and, thus, NEP inhibition augments vasodilatation and natriuresis through increased levels of atrial natriuretic peptide (ANP). By inhibiting the RAS and potentiating the natriuretic peptide system at the same time, combined NEP/ACE inhibitors, the so-called vasopeptidase inhibitors, reduce vasoconstriction and enhance vasodilatation, thereby decreasing peripheral vascular resistance and blood pressure. Within the vessel wall this may lead to a reduction of vasoconstrictor and proliferative mediators, such as angiotensin II and endothelin-1, and may increase local levels of bradykinin as well as natriuretic peptides. Even though first results of both preclinical and clinical studies indicate that combined inhibition of ACE and NEP by vasopeptidase inhibitors represents a promising strategy in the treatment of hypertension and heart failure, angioedema occurs more frequently on vasopeptidase inhibition as compared to ACE inhibition. To establish vasopeptidase inhibition as a novel option in the treatment of cardiovascular disease, further validation of efficacy and safety of this promising therapeutic principle is mandatory.

Endothelial dysfunction and inflammation: What is the link? Cardiovascular disease, resulting from arteriosclerotic remodeling of the vasculature, is the main cause of death in end-stage renal disease (ESRD) patients. Early during the course of arteriosclerosis, endothelial dysfunction can be detected in various vascular beds, including peripheral forearm arteries, as well as the coronary circulation. Furthermore, endothelial dysfunction seems to predict the prognosis of cardiovascular disease. Therefore, the question deserves attention whether endothelial dysfunction is simply a marker of cardiovascular disease, or an active player in the progress of the disease. A possible link between arteriosclerosis, endothelial dysfunction, and cardiovascular disease is increased oxidative stress. Inflammatory processes involved in the pathogenesis of arteriosclerosis enhance vascular O2¯ formation, leading to endothelial dysfunction. An activated renin angiotensin system, together with oxidized low-density lipoprotein, may play a prominent role for enhanced vascular oxidative stress. In this context, the endothelium is not only a target of oxygen radicals, but may also contribute to O2¯ formation. It is the aim of this article to highlight the interplay of inflammation, endothelial dysfunction, and oxidative stress.

Background. Endothelin-1 (ET-1) has been described as a very potent vasoconstrictor. Nevertheless, transgenic mice overexpressing ET-1 have been shown to exhibit normal blood pressure. We thus hypothesized that vascular ET-1 effects may be antagonized by increased activity of other regulatory systems, such as the increase in bioavailability of the endothelial counterpart of ET-1, nitric oxide (NO). Methods. Endothelium-dependent and -independent vascular function was assessed as relaxationucontraction of isolated preconstricted aortic rings to acetylcholine (10 10 –10 4 molul), sodium nitroprusside (10 10 –10 4 molul), ET-1 (10 10 –10 7 molul) and big ET-1 (10 10 –10 7 molul), respectively, in ET-1 transgenic mice and corresponding controls. To unmask the impact of the NO system, we furthermore analysed vessel rings incubated in vitro with the NO-synthase inhibitor L-N G -nitroarginine methyl ester (L-NAME, 10 4 molul). Results. Maximum endothelium-dependent relaxation was enhanced in ET-1 transgenic mice (93"3% vs 84"4% for wild-type littermates; P-0.05) and was inhibited by preincubation with L-NAME in both ET-transgenic mice and wild-type littermates (11"5% vs 9"4% maximum relaxation, respectively). Endothelium-independent relaxation was similar among all groups. Maximum vascular contraction to ET-1 and big ET-1 was reduced in ET-1 transgenic mice (P-0.05 vs wild-type littermates). Preincubation with L-NAME reduced this difference, indicating the involvement of augmented NO availability. Correspondingly, urinary nitrateunitrite excretion was significantly elevated in ET-1 transgenic mice. Conclusions. These data suggest that in transgenic mice overexpressing ET-1, increased NO bioavailability counteracts the contractile potency of elevated ET-1 levels and leads to an improvement of endotheliumdependent relaxation. Thus, in the presence of an activated ET system, up-regulation of NO production may be capable of maintaining vascular tone in a normal range and therefore may prevent the development of hypertension.

Uremic patients suffer to an extremely high degree from cardiovascular disease. Cardiovascular disease results mainly from atherosclerotic remodeling of the arterial system. Inflammation is considered to contribute significantly to development of atherosclerosis, and albeit many different factors may lead to inflammation, generation of enhanced oxidative stress is believed to be an important common feature of pro-inflammatory causes. Studies in the general population without renal disease could clearly show that markers of inflammation, in particular C-reactive protein, predict the cardiovascular risk. In this review article, we discuss the presence and the predictive value of inflammation in patients with end-stage renal disease, and analyze whether uremic patients are exposed to specific pro-inflammatory and pro-oxidative conditions. Particular emphasis is set on oxidative stress induced by oxidatively modified lipoproteins and angiotensin II. Based on pathophysiological considerations valid for uremic patients, we discuss therapeutical options that might help to reduce cardiovascular disease in uremic patients.

The endothelium-derived relaxing factors nitric oxide (NO) and prostacyclin (PGI(2)) are important antithrombotic, relaxant, and antiproliferative agents of the blood vessel wall that exert their intracellular effects primarily via cGMP- and cAMP-dependent protein kinases (cGK, cAK). However, no biochemical marker for their activity in the intact blood vessel is available except for transient increases in the concentration of cGMP and cAMP. Using Western blot analysis and specific antibodies, we show here that phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser239 (P(Ser239)-VASP) in rabbit aorta was detectable only in segments with an intact endothelium, although at least one third of VASP is contained in the remaining vascular wall. In endothelium-denuded aorta, VASP phosphorylation was increased by the NO donor sodium nitroprusside (SNP). Levels of P(Ser239)-VASP, in the presence of endothelium and either SNP or 8-bromo-cAMP, were maximal. VASP phosphorylation elicited by 8-bromo-cAMP was inhibited significantly by the cGK inhibitor Rp-8-Br-PET-cGMPS. Stimulated P(Ser239)-VASP formation was fully reversible, reaching basal levels after 10 min of repeated washouts. Consistent with the important role that the NO/cGMP pathway plays in the formation of P(Ser239)-VASP in rabbit aorta, inhibition of NO synthase by N(omega)-nitro-L-arginine methyl ester (L-NAME; 1 mM) or of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[3,4-a]quinoxalin-1-one (ODQ; 50 microM) almost completely abolished P(Ser239)-VASP formation in endothelium intact blood vessels. These data suggest that vascular P(Ser239)-VASP is primarily regulated by the NO/cGMP pathway and may thus serve as a biochemical marker for the activity state of this essential pathway in endothelial function.

In this study, we analyzed the effect of endothelin-1 (ET-1) on expression of the lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 LOX-1 and on oxLDL uptake in primary cultures of human umbilical vein endothelial cells (HUVEC). LOX-1 mRNA was quantified by standard-calibrated competitive RT-PCR, LOX-1 protein expression by Western analysis and endothelial oxLDL uptake using DiI-labeled oxLDL. ET-1 induces LOX-1 mRNA expression, reaching its maximum after 1 h (160 ± 14% of control, 100 nM ET-1, P < 0.05). This increased ET-1-mediated LOX-1 mRNA expression could be inhibited by endothelin receptor B antagonist BQ-788. In addition, ET-1 stimulates LOX-1 protein expression and oxLDL uptake in HUVEC. The augmented oxLDL uptake by ET-1 is mediated by endothelin receptor B, but not by protein kinases. These data support a new pathophysiological mechanism how locally and systemically increased ET-1 levels could promote LOX-1-mediated oxLDL uptake in human endothelial cells and the development and progression of endothelial dysfunction and atherosclerosis.

Dual effect of oxidized LDL on cell cycle in human endothelial cells through oxidative stress. Background Oxidized low-density lipoprotein (OxLDL) exerts proliferation and apoptosis in vascular cells, depending on its concentration and the exposure time. Various steps in the cell cycle and in the apoptotic signaling cascade are modulated by O − 2 , and OxLDL stimulates vascular O − 2 formation. Here we studied the role of NADPH oxidase, a potential source for O − 2 formation after OxLDL stimulation, in cell proliferation, and we investigated whether OxLDL influences anti-apoptotic genes in cultured human umbilical vein endothelial cells (HUVEC). Methods and Results OxLDL dose-dependently (10 to 300 μg/mL) stimulated O − 2 formation in HUVEC (detected by cytochrome c assay and by chemiluminescence of lucigenin). Low OxLDL concentrations (5 to 10 μg/mL) induced proliferation (detected by 3 H-thymidine incorporation), while higher concentrations (50 to 300 μg/mL) induced apoptotic cell death (detected by Annexin assay and DNA fragmentation). Proliferation was blocked by the antioxidants SOD and catalase and by diphenyleneiodonium (10 μmol/L), an inhibitor of the O − 2 generating NADPH oxidase. In addition, cells transfected with antisense oligonucleotides for NADPH oxidase showed a significantly reduced O − 2 formation after stimulation with OxLDL. The OxLDL effect on apoptosis was also blocked by antioxidants. Since endothelial cells are protected against apoptosis through anti-apoptotic genes, we investigated whether OxLDL overcomes protection against apoptosis through suppression of the anti-apoptotic gene A20, a zinc-finger protein. OxLDL suppressed the expression of A20 in a dose-dependent manner. Conclusion These data indicate that OxLDL has a dual effect on cell cycle in HUVEC, inducing proliferation at low and apoptosis at higher concentrations. Both effects are mediated by O − 2 formation, with NADPH oxidase being a major source for O − 2 . Thus, OxLDL contributes importantly to vascular cellular turnover through the induction of oxidative stress.

Oxidized low-density lipoprotein (OxLDL) exerts proliferation and apoptosis in vascular cells, depending on its concentration and the duration of exposure. Recent studies indicate that [O(2)](-) is involved in cell cycle regulation and that OxLDL stimulates endothelial cells to produce [O(2)](-). This study examined the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a potential source for [O(2)](-) in the proliferation-inducing activity of OxLDL in cultured human umbilical vein endothelial cells (HUVEC). Human LDL was oxidized by Cu(++), and proliferation of HUVEC was detected by 3H-thymidine incorporation. OxLDL (5 microg/ml) caused an increase in proliferation of HUVEC of 250 to 300%. OxLDL-induced proliferation was blocked by addition of the antioxidants superoxide dismutase and catalase, suggesting that enhanced [O(2)](-) formation was involved. Diphenylene iodonium (DPI, 1 microM), an inhibitor of NADPH oxidase, also prevented OxLDL-induced proliferation of HUVEC, indicating that NADPH oxidase was the source for enhanced [O(2)](-) formation. The OxLDL effect was mimicked by lysophosphatidylcholine (LPC, 10 microM), a compound formed during oxidation of LDL. LPC-induced proliferation was also prevented by coincubation with DPI. Treatment of HUVEC with [O(2)](-) generated by the xanthine/xanthine oxidase reaction resulted in proliferation as did treatment with OxLDL. As expected, this stimulation could not be blocked by DPI. With the use of the cytochrome c-assay, it was demonstrated that OxLDL and LPC enhanced [O(2)](-) formation in HUVEC (by factor 3.2 and by factor 3.5, respectively). Supporting the assumption that NADPH oxidase was the enzyme responsible for [O(2)](-) formation, cells transfected with antisense oligonucleotides for NADPH oxidase showed a significantly reduced [O(2)](-) formation after stimulation with OxLDL and LPC. OxLDL and its compound LPC induce proliferation of HUVEC through activation of NADPH oxidase. The active NADPH oxidase generates [O(2)](-), which mediates the proliferative effects.

Background —Oxidatively modified LDL (oxLDL) plays an important role in the development of atherosclerosis. OxLDL effects, eg, foam cell formation, are mediated in part by the classic scavenger receptor, whereas other effects may involve the recently cloned endothelial oxLDL receptor, LOX-1 (lectinlike oxLDL receptor-1), which is distinct from macrophage scavenger receptors. Because the regulation of LOX-1 must still be defined, we investigated whether LOX-1 is regulated by the potentially proatherosclerotic stimulant angiotensin II (Ang II). Methods and Results —Using competitive reverse transcription–polymerase chain reaction (RT-PCR), we quantified mRNA expression of LOX-1 in primary cultures of human umbilical vein endothelial cells (HUVECs). After treatment with Ang II for 3 hours (1 nmol/L to 1 μmol/L), LOX-1 mRNA was concentration-dependently induced (from 6.9±1.4 to 23.1±5.5 relative units [RU] by 1 μmol/L Ang II; P 1 ) receptor antagonist losartan prevented this induction. Incubation of HUVECs with Ang II (100 nmol/L, 3 hours) induced LOX-1 protein expression (212±21% of control level; P P 1 -dependent pathway, reaching its maximum after 24 hours (680±89%; P P Conclusions —We conclude that LOX-1 is regulated by Ang II in vitro and in vivo, that induction of LOX-1 is mediated by the AT 1 receptor, and that repression of LOX-1 by long-term ACE inhibitor treatment may contribute to the antiatherosclerotic potential of this therapy.

The vasomotor and cyclic GMP-elevating activity of YC-1, a novel NO-independent activator of soluble guanylyl cyclase (sGC), was studied in isolated rabbit aortic rings and compared to that of the NO donor compounds sodium nitroprusside (SNP) and NOC 18. Similarly to SNP and NOC 18, YC-1 (0.3–300 μM) caused a concentration-dependent, endothelium-independent relaxation that was greatly reduced by the sGC inhibitor 1-H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ 10 μM; 59% inhibition of dilation induced by 100 μM YC-1) suggesting the activation of sGC as one mechanism of action. Preincubation with YC-1 (3 and 30 μM) significantly increased the maximal dilator responses mediated by endogenous NO in aortic rings that was released upon exposure to acetylcholine, and enhanced the dilator response to the exogenous NO-donors, SNP and NOC 18, by almost two orders of magnitude. Vasoactivity induced by SNP and YC-1 displayed different kinetics as evidenced by a long-lasting inhibition by YC-1 (300 μM) on the phenylephrine (PE)-induced contractile response, which was not fully reversible even after extensive washout (150 min) of YC-1, and was accompanied by a long-lasting elevation of intracellular cyclic GMP content. In contrast, SNP (30 μM) had no effect on the vasoconstrictor potency of PE, and increases in intravascular cyclic GMP levels were readily reversed after washout of this NO donor compound. Surprisingly, YC-1 not only activated sGC, but also affected cyclic GMP metabolism, as it inhibited both cyclic GMP break down in aortic extracts and the activity of phosphodiesterase isoforms 1–5 in vitro. In conclusion, YC-1 caused persistent elevation of intravascular cyclic GMP levels in vivo by activating sGC and inhibiting cyclic GMP break down. Thus, YC-1 is a highly effective vasodilator compound with a prolonged duration of action, and mechanisms that are unprecedented for any previously known sGC activator. British Journal of Pharmacology (1999) 127, 195–203; doi:10.1038/sj.bjp.0702495

Abstract —Physiological levels of laminar shear stress completely abrogate apoptosis of human endothelial cells in response to a variety of stimuli and might therefore importantly contribute to endothelial integrity. We show here that the apoptosis-suppressive effects of shear stress are mediated by upregulation of Cu/Zn SOD and NO synthase. Shear stress-mediated inhibition of endothelial cell apoptosis in response to exogenous oxygen radicals, oxidized LDL, and tumor necrosis factor-α was associated with complete inhibition of caspase-3-like activity, the central effector arm executing the apoptotic cell death program in endothelial cells. Shear stress-dependent upregulation of Cu/Zn SOD and NO synthase blocks activation of the caspase cascade in response to apoptosis-inducing stimuli. These findings establish the upregulation of Cu/Zn SOD and NO synthase by shear stress as a central protective cellular mechanism to preserve the integrity of the endothelium after proapoptotic stimulation.

Hypercholesterolemia is associated with impairment of endothelial function due to increased levels of LDL. In diabetic patients, however, attenuation of endothelial function occurs even under normocholesterolemic conditions. Here we assessed whether glycation of LDL potentiates their influence on endothelial function, with particular emphasis on the oxidizability of LDL and the role of O2-. Human LDL was glycated by dialyzation for 7 days against buffer containing 200 mmol/l glucose, or sham-treated without glucose, and oxidized by incubation with Cu2+. Glycation significantly enhanced the oxidizability of LDL, as detected by diene formation and by electrophoretic mobility (27.5 mm for oxidized LDL vs. 34 mm for oxidized glycated LDL at 20 h of oxidation). Isolated rings of rabbit aorta were superfused with physiological salt solution, and isometric tension was recorded. Incubation of the aortic rings with sham-treated or with glycated LDL, not oxidized, had no influence on acetylcholine-induced, endothelium-dependent relaxation. Exposure of the aortic rings to oxidized non-glycated LDL caused a significant inhibition (30% at 1 microM acetylcholine) of the endothelium-dependent relaxation only in the presence of diethyl-dithiocarbamate (DDC), an inhibitor of the endogenous superoxide dismutase (SOD). Incubation of aortic rings with oxidized glycated LDL attenuated endothelium-dependent relaxation even in the absence of DDC (by 31% at 1 microM acetylcholine). The presence of DDC potentiated the inhibition of relaxation (65% inhibition at 1 microM acetylcholine), and co-incubation with exogenous SOD and catalase prevented the inhibition of relaxation, indicating a mediator role of O2-. Endothelium-independent relaxation induced by forskolin was unaffected by any of the lipoproteins. Using a chemiluminescence assay, significantly increased O2- production of aortic rings pretreated with oxidized glycated LDL (4101 +/- 360 counts/s) in comparison to control rings (753 +/- 81 counts/s) or arteries pretreated with oxidized non-glycated LDL (2358 +/- 169 counts/s) could be detected, suggesting that enhanced NO-inactivation by O2- could be the underlying mechanism for the stronger impairment of endothelium-dependent dilations by oxidized glycated LDL. Glycation increases the oxidizability of LDL and potentiates its endothelium-damaging influence. The likely mechanism for attenuation of endothelium-dependent dilations is increased formation of O2-, resulting in inactivation of nitric oxide. This mechanism may play an important role in diabetic patients and may contribute to disturbed organ perfusion.

Hypercholesterolaemia is common in patients treated with cyclosporin after kidney and heart transplantation; coronary vasculopathy, graft atherosclerosis or cardiovascular complications are the most frequent causes of mortality. Coronary heart disease has been attributed to hypercholesterolaemia and has been identified as a major risk factor of long term graft outcome in patients after kidney transplantation. HMG-CoA reductase inhibitors have been proven to be effective in lowering serum cholesterol concentrations in kidney and heart graft recipients receiving long term cyclosporin immunosuppression, and are therefore the drugs of choice in patients requiring treatment for hypercholesterolaemia after organ transplantation. The hydrophilic HMG-CoA reductase inhibitors, such as pravastatin and fluvastatin, should be distinguished from the lipophilic agents, lovastatin and simvastatin, with regard to toxicity and accumulation. Maximal doses of drugs in the latter group should be avoided, whereas the former have been administered at high dosages over prolonged periods of time without adverse effects. Recent preliminary data indicate that treatment with pravastatin not only decreases serum cholesterol but may have beneficial effects on the incidence, recurrence and severity of rejection episodes after kidney and heart transplantation.

To study whether the activated clotting time (ACT) is a sensitive parameter to monitor anticoagulation with low molecular weight heparin (LMWH) during hemodialysis, ACT, polymorphonuclear granulocyte-elastase, and anti-factor Xa activity were studied during 30 dialysis treatments with LMWH (35 IU/kg body weight bolus; 10 IU/h/kg). Twenty treatments were performed with Hemophan, ten with polysulfone dialyzers. No clinically relevant clotting of dialyzers was observed, but minimal fibrin deposition was found more often in the Hemophan group (50 vs. 30%). Despite continuously elevated anti-factor Xa levels (Hemophan 0.49 +/- 0.03, polysulfone 0.62 +/- 0.01 IU/ml), a significant increase of ACT was only demonstrated 10 min after bolus application in the Hemophan group. Elevated polymorphonuclear granulocyte-elastase levels were demonstrated in the Hemophan group but were linked to the presence of minimal fibrin deposits and not to the dialyzer material. We conclude that ACT is not a sensitive parameter to monitor anticoagulation with standard doses of LMWH.

Atherogenic lipoproteins and reactive oxygen species stimulate renin release from isolated juxtaglomerular (JG) cells. Here we assessed whether stimulation of renin release is mediated by formation of superoxide anion (O2-), and whether the effects of oxidized lipoproteins, like in many other biological systems, can be prevented by the antiatherogenic high density lipoprotein (HDL). Lipoproteins were prepared from human plasma, and JG cells from mouse and rat kidneys. Basal renal activity of JG cells was measured in culture supernatants and cells, and was dose-dependently and significantly stimulated by oxidized LDL (50 and 300 micrograms/ml) and by oxidized Lp(a) (1, 10 and 30 micrograms/ml). Administration of HDL alone had no effect on renin release. However, coincubation with 100 micrograms/ml HDL significantly suppressed oxidized LDL- and oxidized Lp(a)-stimulated renin release. O2- production of JG cells was directly measured using a chemiluminescence assay. Stimulation with 10 micrograms/ml oxidized LDL and oxidized Lp(a) significantly increased the O2- generation of JG cells. In the presence of 5 micrograms/mL HDL, O2- production was reduced to control levels. These data indicate that stimulation of JG cells with oxidized LDL and Lp(a) induces formation of O2-, which may stimulate renin release in an autocrine fashion. Renin release can be prevented by HDL, presumably by preventing the formation of O2-.

Background Hyperlipoproteinemia is associated with impairment of nitric oxide (NO)–mediated, endothelium-dependent dilation in renal arteries. In the present study, we assessed and compared the effects of human lipoprotein(a) and LDL on endothelium-dependent and -independent dilation in vitro. Methods and Results Dilator responses were detected in isolated, saline-perfused, preconstricted arterial segments by a photoelectric device. Acetylcholine-induced, endothelium-dependent dilator responses of rabbit renal arteries were not significantly attenuated after 150 minutes of incubation with native lipoprotein(a) (30 and 100 μg/mL). However, exposure to in vitro oxidized lipoprotein(a) (150 minutes, 30 and 100 μg/mL) suppressed acetylcholine-induced dilator responses in a dose-dependent manner. At similar concentrations, native and oxidized LDL had no effect. Endothelium-independent dilations induced by the NO-donor sodium nitroprusside were also impaired by oxidized lipoprotein(a), whereas forskolin-induced dilator responses were unaffected, indicating that smooth muscle dilator capacity was not impaired. Attenuation of dilator responses by oxidized lipoprotein(a) was potentiated in the presence of superoxide dismutase (SOD). The SOD effect was completely blunted by coincubation with catalase (100 U/mL) or deferoxamine. In the absence of SOD, catalase or deferoxamine had no effect on dilator responses. Using a chemiluminescence assay, we could detect increased O 2 − production by arteries pretreated with oxidized lipoprotein(a), which suggested that enhanced NO inactivation by O 2 − could be the underlying mechanism for impairment of endothelium-dependent dilations. Conclusions These data indicate that oxidized lipoprotein(a) impairs endothelium-dependent dilation and is more potent than oxidized LDL in this effect. The mechanism of the impairment may involve formation of O 2 − and inactivation of NO.