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To determine the therapeutic efficiency of percutaneous revascularization in renal artery stenosis (RAS), as well as the role of comprehensive factors such as patient selection and degree of artery stenosis, on clinical outcome. 101 patients with hemodynamically relevant RAS underwent percutaneous angioplasty (PTA). 65.7 % were male (mean age: 64 years; range: 18-84). The clinical data was retrospectively analyzed. The serum creatinine (Cr), glomerular filtration rate (GFR), and blood pressure (BP) levels pre- and postprocedural, between 6 months and 1 year, were retrospectively collected and statistically analyzed. Follow-up data was available in 34 (33.7 %) and 28 patients (27.7 %) for Cr and MAP, respectively. A significant drop in mean arterial pressure (MAP) was observed on follow-up (mean -5.27 mmHg). Higher baseline Cr and MAP values showed a more pronounced drop in the follow-up (Cr: p 0.002; difference to baseline -0.25 mg/dL, 95 %CI:-0.36, -0.07 and BP p 0.001; diff. to baseline -0.72 mmHg; 95 %CI: -1.4, -0.40). There was no association between comorbidities, gender, and degree of stenosis with renal and BP outcome. No significant improvement in renal function was observed on follow-up (mean Cr drop: -0.015 mg/dL). The age group 51-60 years showed a significant improvement in BP (p 0.030; diff. to baseline -19.2 mmHg; 95 %CI: -34, -4.3). There was a slight reduction in antihypertensive medication following angioplasty (0.2 fewer). Minor complications were recorded in five procedures (4.9 %). Percutaneous renal artery revascularization in the presence of atherosclerotic RAS is a safe procedure associated with a significant drop in post-procedural BP. No significant improvement in renal function was observed. Further prospective studies focused on patient selection are necessary. · Percutaneous stent angioplasty in renal artery stenosis is associated with a significant improvement in post-procedural blood pressure control.. · There is no improvement in renal function after percutaneous stent angioplasty for renal artery stenosis (RAS).. · Percutaneous stent angioplasty is a safe procedure..· Guerreiro H, Avanesov M, Dinnies S et al. Efficiency of Percutaneous Stent Angioplasty in Renal Artery Stenosis - 15 Years of Experience at a Single Center. Fortschr Röntgenstr 2021; 193: 298 - 304. Bestimmung der therapeutischen Effizienz der perkutanen Revaskularisation bei Nierenarterienstenose (RAS) sowie der Rolle umfassender Faktoren wie Patientenauswahl und Grad der Arterienstenose für das klinische Ergebnis. Bei 101 Patienten mit hämodynamisch relevanter RAS wurde eine perkutane Angioplastie (PTA) durchgeführt. 65,7 % waren männlich, das Durchschnittsalter betrug 64 Jahre (Bereich: 18–84). Die klinischen Daten wurden retrospektiv analysiert. Serumkreatinin (Cr), glomeruläre Filtrationsrate (GFR) und Blutdruckwerte (BP) prä- und postinterventionell sowie zwischen 6 Monaten und einem Jahr wurden retrospektiv erhoben und statistisch analysiert. Follow-up-Daten waren bei 34 (33,7 %) und 28 Patienten (27,7 %) jeweils für Cr und BP verfügbar. Bei der Nachuntersuchung wurde ein signifikanter Abfall des mittleren arteriellen Drucks (MAP) beobachtet (Mittelwert –5,27 mmHg). Höhere Cr- und MAP-Basiswerte zeigten einen ausgeprägteren Abfall im Follow-up (Cr: p = 0,002; Differenz zum Basiswert –0,25 mg/dl, 95 %-KI –0,36 bis-0,07 und BP p 0,001; Differenz zum Basiswert –0,72mmHg; 95 %-KI –1,4 bis –0,40). Es bestand kein Zusammenhang zwischen Komorbiditäten, Geschlecht und Stenosegrad mit dem Nieren- und Blutdruckergebnis. Beim Follow-up wurde keine signifikante Verbesserung der Nierenfunktion beobachtet (mittlerer Cr-Abfall: –0,015 mg/dl). In der Altersgruppe 51–60 Jahre zeigte sich eine signifikante Verbesserung des Blutdrucks (p = 0,030; Differenz zum Ausgangswert –19,2mmHg; 95 %-KI –34 bis –4,3). Die antihypertensive Medikation nach der Angioplastie wurde leicht reduziert (0,2 weniger). Unbedeutende Komplikationen wurden bei 5 Eingriffen festgestellt (4,9 %). Die perkutane Nierenarterienrevaskularisierung bei vorliegender atherosklerotischer RAS ist ein sicheres Verfahren, das mit einem signifikanten Abfall des postprozeduralen Blutdrucks einhergeht. Eine signifikante Verbesserung der Nierenfunktion wurde nicht beobachtet. Weitere prospektive Studien zur Patientenauswahl sind notwendig. · Die perkutane Stentangioplastie bei Nierenarterienstenose ist mit einer signifikanten Verbesserung der postprozeduralen Blutdruckkontrolle verbunden.. · Es gab keine Verbesserung der Nierenfunktion nach der perkutanen Stentangioplastie bei Nierenarterienstenose (RAS).. · Die perkutane Stentangioplastie ist ein sicheres Verfahren..

Hyponatremia is a common condition affecting hospitalized and ambulatory patients as well. The clinical spectrum of hyponatremia can range from asymptomatic laboratory findings to severely symptomatic conditions such as acute epileptic seizures. Etiologies of hyponatremia include excessive intake of solute-free fluids, side-effects of medication, diseases associated with hypervolemic states such as congestive heart failure, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH).As hyponatremia can be a potentially life-threatening condition, it requires an efficient management with the goal of identifying the etiology and to subsequently provide adequate treatment, while avoiding treatment-related adverse effects such as overcorrection and pontine myelinolysis. This article summarizes the pathophysiology and differential diagnosis, as well as useful diagnostic tests and therapy of hyponatremia in a practice-oriented manner.

Weltweit haben mehr als eine Milliarde Menschen eine arterielle Hypertonie. Allein in Deutschland ist ein Drittel der Bevolkerung betroffen, Tendenz steigend. Die moglichen Folgen sind gravierend: Neben irreparablen Organschaden und erhohtem Mortalitatsrisiko verursacht Bluthochdruck auch enorme Krankheits- und volkswirtschaftliche Kosten. Deshalb gilt fur alle Akteure im Gesundheitssystem: Es ist Zeit zu handeln.

The Western diet is rich in salt, which poses various health risks. A high-salt diet (HSD) can stimulate immunity through the nuclear factor of activated T cells 5 (Nfat5)-signaling pathway, especially in the skin, where sodium is stored. The kidney medulla also accumulates sodium to build an osmotic gradient for water conservation. Here, we studied the effect of an HSD on the immune defense against uropathogenic E. coli-induced pyelonephritis, the most common kidney infection. Unexpectedly, pyelonephritis was aggravated in mice on an HSD by two mechanisms. First, on an HSD, sodium must be excreted; therefore, the kidney used urea instead to build the osmotic gradient. However, in contrast to sodium, urea suppressed the antibacterial functionality of neutrophils, the principal immune effectors against pyelonephritis. Second, the body excretes sodium by lowering mineralocorticoid production via suppressing aldosterone synthase. This caused an accumulation of aldosterone precursors with glucocorticoid functionality, which abolished the diurnal adrenocorticotropic hormone-driven glucocorticoid rhythm and compromised neutrophil development and antibacterial functionality systemically. Consistently, under an HSD, systemic Listeria monocytogenes infection was also aggravated in a glucocorticoid-dependent manner. Glucocorticoids directly induced Nfat5 expression, but pharmacological normalization of renal Nfat5 expression failed to restore the antibacterial defense. Last, healthy humans consuming an HSD for 1 week showed hyperglucocorticoidism and impaired antibacterial neutrophil function. In summary, an HSD suppresses intrarenal neutrophils Nfat5-independently by altering the local microenvironment and systemically by glucocorticoid-mediated immunosuppression. These findings argue against high-salt consumption during bacterial infections.

A key finding supporting a causal role of the immune system in the pathogenesis of hypertension is the observation that RAG1 knockout mice on a C57Bl/6J background (B6.Rag1 −/ − ), which lack functional B and T cells, develop a much milder hypertensive response to Ang II (angiotensin II) than control C57Bl/6J mice. Here, we report that we never observed any Ang II resistance of B6.Rag1 −/− mice purchased directly from the Jackson Laboratory as early as 2009. B6.Rag1 −/− mice displayed nearly identical blood pressure increases monitored via radiotelemetry and hypertensive end-organ damage in response to different doses of Ang II and different levels of salt intake (0.02%, 0.3%, and 3% NaCl diet). Similarly, restoration of T-cell immunity by adoptive cell transfer did not affect the blood pressure response to Ang II in B6.Rag1 −/− mice. Full development of the hypertension-resistant phenotype in B6.Rag1 −/− mice appears to depend on the action of yet unidentified nongenetic modifiers in addition to the absence of functional T cells.

The role of CX3CR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CX3CR1 in hypertensive renal and cardiac injury. Expression of CX3CR1 was determined using CX3CR1GFP/+ mice that express a green fluorescent protein (GFP) reporter in CX3CR1+ cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45+ cells expressed CX3CR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%), and T cells (10%). With the use of confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CX3CR1 in hypertensive end-organ injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of angiotensin II (ANG II, 1.5 ng·g−1·min−1) and a high-salt diet in wild-type ( n = 15) and CX3CR1-deficient mice ( n = 18). CX3CR1 deficiency reduced the number of renal dendritic cells and increased the numbers of renal CD11b/F4/80+ macrophages and CD11b/Ly6G+ neutrophils in ANG II-infused mice. Surprisingly, CX3CR1-deficient mice exhibited increased albuminuria, glomerular injury, and reduced podocyte density in spite of similar levels of arterial hypertension. In contrast, cardiac damage as assessed by increased heart weight, cardiac fibrosis, and expression of fetal genes, and matrix components were not different between both genotypes. Our findings suggest that CX3CR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CX3CR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury.

The (pro)renin receptor [(P)RR], also known as ATP6AP2 [ATPase 6 accessory protein 2], is highly expressed in the brain. ATP6AP2 plays a role in early brain development, adult hippocampal neurogenesis and in cognitive functions. Lack of ATP6AP2 has deleterious effects, and mutations of ATP6AP2 in humans are associated with, e.g. X-linked intellectual disability. However, little is known about the effects of over-expression of ATP6AP2 in the adult brain. We hypothesized that mice over-expressing ATP6AP2 in the brain might exhibit altered neuroanatomical features and behavioural responses. To this end, we investigated heterozygous transgenic female mice and confirmed increased levels of ATP6AP2 in the brain. Our data show that over-expression of ATP6AP2 does not affect adult hippocampal neurogenesis, exercise-induced cell proliferation, or dendritic spine densities in the hippocampus. Only a reduced ventricular volume on the gross morphological level was found. However, ATP6AP2 over-expressing mice displayed altered exploratory behaviour with respect to the hole-board and novel object recognition tests. Moreover, primary adult hippocampal neural stem cells over-expressing ATP6AP2 exhibit a faster cell cycle progression and increased cell proliferation. Together, in contrast to the known deleterious effects of ATP6AP2 depletion, a moderate over-expression results in moderate behavioural changes and affects cell proliferation rate in vitro.

To evaluate the kidneys of patients with haemolytic uraemic syndrome (HUS) using diffusion-weighted imaging (DWI) and Doppler ultrasound (US) compared with healthy controls. Fifteen patients (mean age 33.3 years; three male; 12 female) with diarrhoea-positive HUS and 15 healthy volunteers were prospectively evaluated with DWI and Doppler US. A total apparent diffusion coefficient (ADCTOT), and ADCs predominantly reflecting microperfusion (ADCLOW) and diffusion (ADCHIGH) were calculated. Doppler US evaluated renal vascularity and flow. When compared with controls, kidneys affected by HUS showed reduced cortical ADC values (ADCTOT 1.79±0.22 vs. 2.04±0.1x10-3 mm2/s, P 0.001), resulting in either low corticomedullary differences (11/15 patients) or an inverted corticomedullary pattern (4/15 patients). Reduction of cortical ADC values was associated with a decrease of cortical vascularity on Doppler US (ADCTOT, P

To investigate the effects of renal denervation (RDN) on left ventricular (LV) mass, myocardial strain and diastolic function in patients with treatment-resistant arterial hypertension by cardiac magnet resonance imaging on a 12-month follow-up. Sixteen patients (38% female) were examined before and 12 months after RDN. LV morphology and strain were analyzed. Diastolic function was determined by early (EPFR) and atrial peak filling rates (APFR) derived from differential volume–time-curve analysis. Clinical visits included 24-h ambulant blood pressure monitoring (ABPM). Twelve months after RDN LV mass decreased from 80 ± 21 g/m2 to 74 ± 20 g/m2 (P

BACKGROUND AND PURPOSE: The adaptive immune response and IL‐17A contribute to renal damage in several experimental models of renal injury. EXPERIMENTAL APPROACH: To evaluate the role of the adaptive immune response, 5/6 nephrectomy was performed in wildtype DBA/1J mice and in recombination‐activating gene‐1 (RAG‐1) deficient mice that lack B and T‐cells. To assess the role of IL‐17A, we carried out 5/6 nephrectomy in IL‐17A deficient mice. Flow cytometric analysis, immunohistochemistry and RT‐PCR were used. KEY RESULTS: Infiltration of CD3(+) T‐cells in the remnant kidney was increased after 5/6 nephrectomy in wildtype mice, along with a robust induction of IL‐17A production in CD4(+) T and γδ T‐cells. After 5/6 nephrectomy, wildtype mice developed albuminuria in the nephrotic range over 10 weeks. This was accompanied by severe glomerular sclerosis and tubulointerstitial injury, and as well as renal mRNA expression of markers of inflammation and fibrosis (the chemokine CCL2, plasminogen activator inhibitor‐1; PAI‐1 and neutrophil gelatinase‐associated lipocalin; NGAL). Unexpectedly, RAG‐1 deficient mice and IL‐17A deficient mice developed renal injury, similar to that in wildtype mice. No differences were found for albuminuria, glomerular sclerosis, tubulointerstitial injury and mRNA expression of CCL2, PAI‐1 and NGAL. Mortality did not differ between the three groups. CONCLUSIONS AND IMPLICATIONS: Numbers of CD3(+) T‐cells and IL‐17A(+) lymphocytes infiltrating the kidney were increased after 5/6 nephrectomy. In contrast to other experimental models of renal injury, genetic deficiency of the adaptive immune system or of IL‐17A did not attenuate induction or progression of chronic kidney disease after 5/6 nephrectomy. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc

OBJECTIVES The aim of this double-blind, randomized, sham-controlled study was to verify the blood pressure (BP)-lowering efficacy of externally delivered focused ultrasound for renal denervation (RDN). BACKGROUND Nonrandomized, first proof-of-concept study and experimental evidence suggested that noninvasive techniques of RDN emerged as an alternative approach of RDN to invasive technologies. METHODS WAVE IV, an international, randomized (1 : 1) sham-controlled, double-blind prospective clinical study, was prematurely stopped. Patients were enrolled if office BP was at least 160 mmHg and 24-h ambulatory BP was at least 135 mmHg, while taking three or more antihypertensive medications. The treatment consisted of bilateral RDN using therapeutic levels of ultrasound energy and the sham consisted of bilateral application of diagnostic levels of ultrasound energy. RESULTS In the 81 treated patients neither changes in office BP at 12 and 24 weeks, nor changes in 24-h ambulatory BP at 24-week follow-up visit differed between the two groups significantly. Of note, no safety signal was observed. Adherence analysis disclosed full adherence in 77% at baseline and 82% at 6 months' follow-up visit. Post hoc analysis revealed that stricter criteria for stabilization of BP at baseline were associated with a numerically greater change in 24-h ambulatory BP in the RDN group than in the sham group. CONCLUSION Our data did not prove that antihypertensive efficacy of the externally delivered focused ultrasound for RDN was greater than the sham effect. Stabilization of BP at baseline was identified as an important determinant of BP changes.

BACKGROUND Although treatment-resistant hypertension (RH) is a serious burden on population health, there exists uncertainty about its prevalence. Hence, the objectives of this work were to systematically review and critically appraise the literature and to conduct a meta-analysis on the prevalence of RH in treated hypertensive populations. METHODS PubMed, Cochrane Library, CRD York databases, and study bibliographies were systematically searched for observational and interventional studies that report disease frequency in adult populations. The pooled prevalence was obtained through random-effect modeling. Furthermore, quality assessment, publication bias diagnostics, meta-regression, subgroup analysis by sex, and sensitivity analysis were performed. RESULTS Out of 318 retrieved studies, 20 observational studies and 4 randomized control trials (RCTs) with a total population of 961,035 were included. The random-effect method for observational studies and RCTs yielded RH prevalence ratios of 13.72% (95% confidence interval (CI) = 11.19%-16.24%) and 16.32% (95% CI = 10.68%-21.95%), respectively. Yet, most studies were incapable of ruling out pseudo-resistance caused by white-coat effect, poor medication adherence, and suboptimal dosing. Differences in RH prevalence by sex were negligible. Meta-regression analysis showed that study-level characteristics had no statistically significant influence on RH prevalence. The inclusion of further studies in the sensitivity analysis concurred with the baseline results (13.19%; 95% CI = 10.89%-15.49%). CONCLUSIONS Researchers should enhance comparability of future empirical evidence through homogeneous methodologies and comparable baseline populations. This meta-analysis concludes that RH is a frequent phenomenon and further harmonization in terms of RH definition and measurement would be necessary to clearly distinguish true treatment resistance from pseudo-resistance.

Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.

Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken beta-actin promoter. Mice were backcrossed in the C57BI/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25- to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.

Background and objective: The antihypertensive effects of the direct renin inhibitor aliskiren last substantially longer after treatment withdrawal than expected based upon its plasma half-life. This may be attributable to drug accumulation in the kidney as recently shown in rats and mice. Since aliskiren binds to renin we examined in the present study whether this accumulation depends on the renin content of the kidney.Methods: For this we measured the aliskiren concentration in the kidney of wild-type as well as AT1a receptor(-/-) and Ren1c(-/-) mice. AT1a receptor(-/-) mice overexpress renin due to the lack of angiotensin II-mediated negative feedback, whereas Ren1c(-/-) mice lack renal renin expression.Results: Accumulation of aliskiren was found in the kidney of wild-type mice. However, renal accumulation was neither influenced by the overexpression nor by the absence of renin in the kidney. It was recently shown that the effects of aliskiren can be blocked by a handle region peptide, which inhibits the nonproteolytic activation of prorenin bound to the (pro)renin receptor. To investigate whether this putative (pro)renin receptor blocker influences renal aliskiren accumulation, we administered the blocker in addition to aliskiren. No influence on renal aliskiren accumulation was observed.Conclusion: These data confirm accumulation of aliskiren in the murine kidney and demonstrate that neither renin nor (pro)renin receptor-bound prorenin are major players in this process.

Fraune C, Lange S, Krebs C, Holzel A, Baucke J, Divac N, Schwedhelm E, Streichert T, Velden J, Garrelds IM, Danser AH, Frenay A, van Goor H, Jankowski V, Stahl R, Nguyen G, Wenzel UO. AT(1) antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease. Am J Physiol Renal Physiol 303: F1037-F1048, 2012. First published July 11, 2012; doi:10.1152/ajprenal.00672.2011.-The role of the renin-angiotensin system in chronic kidney disease involves multiple peptides and receptors. Exerting antipodal pathophysiological mechanisms, renin inhibition and AT1 antagonism ameliorate renal damage. However, it is unclear which mechanism exerts better nephroprotection. We compared the renin inhibitor aliskiren with the AT1 antagonist losartan in mice with chronic kidney disease due to renal ablation. Doses were adjusted to equipotent inhibition of the renin-angiotensin system, determined via a dose-response quantifying plasma and renal renin expression. Six-week treatment with either 500 mg/l drinking water losartan or 50 mg.kg(-1).day(-1) aliskiren significantly decreased albuminuria, glomerular damage, and transcription rates of renal injury markers to a similar extent. An array analysis comparing renal gene expression of losartan- and aliskiren-treated mice evaluating > 34,000 transcripts demonstrated regulation for 14 genes only, with small differences. No superior nephroprotection was found by combining losartan and aliskiren. Compared with plasma concentrations, aliskiren accumulated similar to 7- to 29-fold in the heart, liver, lung, and spleen and similar to 156-fold in the kidney. After withdrawal, plasma concentrations dropped to zero within 24 h, whereas renal tissue concentrations declined slowly over days. Withdrawal of aliskiren in mice with chronic kidney disease revealed a significantly delayed re-increase in albuminuria compared with withdrawal of losartan. This study demonstrates equieffective nephroprotection of renin inhibition and AT1 antagonism in mice with chronic kidney disease without additional benefit of combination therapy. These observations underscore the pivotal role of targeting ANG II to reduce renal injury.

BACKGROUND CCR5 is expressed on infiltrating T cells in hypertensive mice and CCR5 antagonists reduce hypertension making CCR5 an interesting target in treatment of hypertension. METHODS To evaluate the role of CCR5 in hypertensive renal and cardiac end-organ damage, we induced hypertension with desoxycorticosterone acetate (DOCA) and angiotensin II (Ang II) in wild-type (WT) and CCR5-deficient mice. RESULTS CCR5 expression was increased in renal cortex and cardiac tissue as measured by quantitative PCR. Systolic blood pressure and renal function did not differ between hypertensive CCR5(-/-) and WT mice. DOCA + Ang II induced massive albuminuria and glomerular injury but no difference was found between CCR5(-/-) and WT mice. In addition, no difference was found for renal inflammation as measured by infiltrating T cells, macrophages, and CCL2 expression. The renal expression of the CCR5 ligands, CCL3, and CCL5 was increased in the kidney of hypertensive mice. For CCL3 the increase was significantly higher in CCR5(-/-) than in WT mice. DOCA + Ang II induced cardiac damage as assessed by heart weight, cardiac fibrosis as well as expression of fetal and matrix components but no significant difference was found between CCR5(-/-) and WT mice. CONCLUSIONS CCR5 deficiency does not influence hypertensive renal and cardiac end-organ damage. Cells that infiltrate by expression of CCR5 are either not pathogenic or CCR5-positive leukocytes can migrate via alternative chemokine receptors. Beneficial effects of CCR5 antagonists in hypertension are most likely due to unspecific effects of the antagonists. Possibly, other chemokine receptors in concert with CCR5 are important for hypertensive injury.

Background: Endothelial dysfunction has recently been demonstrated in obstructive sleep apnea (OSA), but the underlying mechanisms are not entirely understood. Oxidative stress is a typical feature of OSA. Objectives: We investigated the influence of oxidative stress and continuous positive airway pressure (CPAP) on microvascular endothelial function in OSA. Methods: Endothelial function of forearm resistance vessels was assessed by strain gauge venous occlusion plethysmography after intra-arterial infusion of the endothelium-independent vasodilator sodium nitroprusside (1.6, 3.2, and 4.0 µg/min) and the endothelium-dependent vasodilator acetylcholine (Ach, 15, 30 and 40 µg/min) in patients with (n = 11) and without (n = 8) OSA (apnea-hypopnea index ≧15/h). These measurements have been repeated after local intra-arterial infusion of the antioxidant vitamin C (25 µg/min). Furthermore, 6 patients have been reevaluated after 6 months of OSA treatment. Results: Patients with OSA demonstrated impaired endothelial function compared to those without OSA. Thus, related to baseline flow, the increase in forearm blood flow induced by Ach was blunted in patients with OSA (148.7 ± 29.7% in OSA vs. 233.6 ± 45.7% in controls, p = 0.001). This difference, however, was abolished by co-infusion of vitamin C. Endothelial function markedly improved following treatment in 5 of 6 OSA patients. Conclusions: This study strongly suggests that microvascular endothelial function is affected by OSA predominantly through increased oxidative stress, and treatment of OSA may improve endothelial function mainly by reducing oxidative stress. The role of oxidative stress-induced endothelial dysfunction as a potential promoter of atherosclerosis and an increased cardiovascular risk in patients with OSA should be investigated in further controlled studies.

Background/Aims: The interaction of ‘advanced glycation end products’ (AGEs) and their receptor ‘RAGE’ plays an important role in diabetic nephropathy. We have previously found that in cultured differentiated podocytes, angiotensin II (ANG II) induces RAGE expression via an AT2 receptor-mediated pathway. Methods: To further confirm our results in an in vivo study, AT2 receptor knockout mice (AT2–/–) and wild-type mice were infused with ANG II by osmotic minipumps for 14 days. Results: As shown by immunohistochemistry, ANG II treatment of wild-type animals (C57BL6) allowed a significantly increased RAGE expression in renal podocytes in comparison to sham-operated C57BL6 mice. In contrast, RAGE expression in podocytes of ANG II-treated knockout mice (AT2–/–) was only moderately higher than in control animals, but significantly lower than in ANG II-treated wild-type mice. For the AGE species NΕ-carboxymethyllysine, a similar immunohistochemical staining pattern was found. There was no significant change in glomerular AT1a receptor expression. However, no difference in RAGE mRNA expression could be found between ANG II-infused wild-type and AT2–/– animals by real-time PCR using whole kidney mRNA, presumably due to the low abundance of podocyte mRNA in these preparations. No effects were seen on glomerular apoptosis. Conclusion: These data support the fact that ANG II-mediated RAGE induction in podocytes occurs via AT2 receptors. The present findings may suggest that not all ANG II-mediated changes in diabetic nephropathy can be treated with AT1 receptor blockers.

Als Multisystemerkrankungen konnen systemische Amyloidosen durch renale Symptome klinisch apparent werden; u. a. sind sie wichtige Differenzialdiagnosen des nephrotischen Syndroms. Sie konnen zu irreversiblen Nierenschadigungen fuhren. Ziel der Amyloidosebehandlung ist die Stilllegung der Quelle der Amyloidvorstufen durch Beherrschung der Grunderkrankung. Ansatze mit Substanzen, welche die Ablagerung von Amyloid hemmen bzw. dessen Auflosung beschleunigen, befinden sich noch in der Erprobung. Bei den deutlich selteneren hereditaren Amyloidosen, die auf fibrillogenen Mutationen verschiedener fur Proteine kodierender Gene beruhen, und masgeblich hepatischer Synthese des Vorlauferproteins ist eine Lebertransplantation eine therapeutische Option.

Angiotensin II (Ang II) activates at least two receptors, AT1 and AT2, with the majority of its effects-such as vasoconstriction, inflammation, and matrix deposition-mediated by the AT1 receptor. It is thought that the AT2 receptor counteracts these processes; however, recent studies have found proinflammatory and hypertrophic effects of this receptor subtype. To identify the physiological roles of the AT2 receptor in chronic kidney disease, we performed renal ablation in AT2 receptor knockout and wild-type mice. Renal injury caused a greater impairment of renal function, glomerular injury, albuminuria, and mortality in the knockout mice than in the wild-type mice. There was increased fibronectin expression and inflammation in the knockout mice, as shown by augmented monocyte/macrophage infiltration and higher chemokine monocyte chemotactic protein-1 (MCP-1) and RANTES expression in the remnant kidney. The higher mortality and renal morbidity of the knockout mice was not due to differences in systemic blood pressure, glomerular volume, AT1 receptor, renin, or endothelial nitric oxide synthase expression. Whether activation of the AT2 receptor will have therapeutic benefit in chronic kidney disease will require further study.

Rho kinase signaling regulates inflammatory cell migration and chemokine production. We therefore investigated the mechanisms of Rho-kinase-dependent inflammation in lipopolysaccharide (LPS)-induced renal failure. C57/BL6 mice received intraperitoneal LPS with or without daily treatment with specific Rho kinase inhibitors (Y-27632 or HA-1077; 5 mg/kg). Rho kinase inhibitors were applied in a preventive (12 or 1 h before LPS) or a therapeutic (6 h after LPS) scheme. Both protected renal function and decreased tubular injury in LPS-treated mice. Enhanced Rho kinase activity was inhibited by HA-1077 in capillary endothelial cells, inflammatory cells, and tubuli by analysis of Rho kinase substrate phosphorylation. Early neutrophil influx was reduced by HA-1077 without reduction of the proinflammatory cytokine TNFalpha. In contrast, HA-1077 decreased the influx of monocytes/macrophages coinciding with reduced expression of the NF-kappaB-regulated chemokines CCL5 and CCL2. We therefore examined NF-kappaB signal transduction and found that NF-kappaB p65 phosphorylation and nuclear translocation were reduced by Rho kinase inhibition. IkappaBalpha degradation was not altered during the first 6 h but was reduced by HA-1077 at later time points. NF-kappaB p50-deficient mice were similarly protected from renal injury by Rho kinase inhibition further supporting the prominent role for p65 in Rho kinase inhibition. Together, these data suggest that Rho kinase inhibition by preventive or therapeutic treatment effectively reduced endotoxic kidney injury in part by attenuation of NF-kappaB p65 activation.

The chemokine receptor CCR5 is predominantly expressed on monocytes and Th1-polarized T cells, and plays an important role in T cell and monocyte recruitment in inflammatory diseases. To investigate the functional role of CCR5 in renal inflammation, we induced a T cell-dependent model of glomerulonephritis (nephrotoxic serum nephritis) in CCR5−/− mice. Induction of nephritis in wild-type mice resulted in up-regulation of renal mRNA expression of the three CCR5 chemokine ligands, CCL5 (15-fold), CCL3 (4.9-fold), and CCL4 (3.4-fold), in the autologous phase of the disease at day 10. The up-regulated chemokine expression was paralleled by infiltration of monocytes and T cells, followed by renal tissue injury, albuminuria, and loss of renal function. Nephritic CCR5−/− mice showed a 3- to 4-fold increased renal expression of CCL5 (61.6-fold vs controls) and CCL3 (14.1-fold vs controls), but not of CCL4, in comparison with nephritic wild-type mice, which was accompanied by augmented renal T cell and monocyte recruitment and increased lethality due to uremia. Furthermore, CCR5−/− mice showed an increased renal Th1 response, whereas their systemic humoral and cellular immune responses were unaltered. Because the CCR5 ligands CCL5 and CCL3 also act via CCR1, we investigated the effects of the pharmacological CCR1 antagonist BX471. CCR1 blockade in CCR5−/− mice significantly reduced renal chemokine expression, T cell infiltration, and glomerular crescent formation, indicating that increased renal leukocyte recruitment and consecutive tissue damage in nephritic CCR5−/− mice depended on functional CCR1. In conclusion, this study shows that CCR5 deficiency aggravates glomerulonephritis via enhanced CCL3/CCL5-CCR1-driven renal T cell recruitment.

BACKGROUND AND OBJECTIVE Despite official guidelines on the diagnosis and treatment of hypertensive crisis, the extent to which they are being followed in routine medical practice is unknown. This study was undertaken to discover how hospital doctors were handling cases of hypertensive crisis (HC). MATERIALS AND METHODS Physicians were requested to participate in a multiple-choice questionnaire study, relating to the diagnosis of HC, any emergency diagnosis and choice of antihypertensive drugs, these questionnaires to be distributed among the medical staff. Ultimately 463 questionnaires (one per doctor) were sent out and 325 were completed (response rate of 70%). RESULTS The most frequently mentioned blood pressure values characteristics for HC were > 200 systolic and > 120 diastolic. 160/90 was given most often as the therapeutic goal, which most doctors wanted to reach in an HC within 30 to 60 min. The calcium-antagonist nifedipine was the drug of first choice for almost all clinical presentations. Second was intravenously urapidil, an alpha-agonist. Nitroglycerin was named as first choice only for pulmonary oedema or myocardial infarction. In everyone of the stated conditions most doctors were eager to avoid using beta-blockers. As for the drug of first choice in associated myocardial infarction, 111 doctors named nifedipine, 28 wanted to avoid it and 45 considered it contraindicated. CONCLUSION These data show a marked discrepancy between recommended guidelines and actual practice in the management of hypertensive crisis.

Background : Hypertension is a cardiovascular risk factor commonly associated with endothelial dysfunction and increased renal vascular resistance. Angiotensin receptor blockers (ARBs) may beneficially affect these parameters via antagonism of angiotensin type 1 (AT1) receptor-mediated vasoconstriction and vascular superoxide production. We therefore investigated whether the new ARB telmisartan improves endothelial function and renal vascular resistance in patients with essential hypertension. Methods : Thirty-seven patients with essential hypertension were randomized to receive telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks in a prospective, parallel group study. Brachial artery flow-mediated (endothelium-dependent) dilation (FMD) and renal vascular resistance index (RVRI) were evaluated using high-resolution ultrasound before, at 3 weeks (low dose), and at 6 weeks (high dose) after initiation of treatment. Results : At baseline, FMD and RVRI did not significantly differ between treatment groups. After 3 weeks of treatment neither treatment significantly changed FMD or RVRI. After 6 weeks of treatment, patients randomized to receive telmisartan alone or the combination, but not those treated with nisoldipine alone, displayed a significantly improved FMD, whereas RVRI values again were not significantly different as compared to those at baseline. Conclusion : In our study cohort of patients with essential hypertension, treatment with telmisartan improved FMD but did not change RVRI. Future studies will demonstrate whether this telmisartan-induced effect may contribute to a blood pressure-independent reduction in cardiovascular morbidity.

The present study examined the pathogenesis of interstitial inflammation and fibrosis in antihypertensively treated rats with two-kidney, one-clip hypertension. Hypertensive rats were randomized into four groups: no treatment and moderate, intermediate, and intensified lowering of blood pressure with increasing doses of a vasopeptidase inhibitor for 6 wk. The vasopeptidase inhibitor dose dependently lowered blood pressure. The tubulointerstitial damage was accompanied by a diffuse infiltration of mononuclear cells and circumscript mononuclear inflammatory cell cluster formation consisting mainly of T cells and to a lesser degree of macrophages and B cells. Real-time PCR analyses showed a dose-dependent induction of MCP-1 and the Th1-type chemokines IP10 and Mig as well as their receptor CXCR3 and the Th1 cytokine IFN-γ. In situ hybridization and laser microdissection revealed a strong expression of these Th1-associated transcripts in the clusters and, in the case of MCP-1, also diffusely in the interstitium. The inflammation was accompanied by the appearance of myofibroblasts and synthesis of the fibrogenic factor plasminogen activator inhibitor-1 as well as the collagenase matrix metalloproteinase-2, leading to collagen I upregulation and interstitial scarring. No inflammation or fibrosis was found in normotensive rats treated with the vasopeptidase inhibitor. The renal injury in the clipped kidney is accompanied by compartment-specific chemokine expression and cell cluster formation of Th1 specificity associated with upregulation of fibrogenic proteins and matrix metalloproteinases. These findings suggest that the Th1 chemokines IP10 and Mig as well as their receptor CXCR3 are potential targets for therapeutic interventions in ischemic nephropathy.

Background. The kidney plays an important role in the metabolism of lipoproteins, but renal cells are also a target of lipids under pathophysiological conditions contributing to organ damage and progression of disease. The majority of studies has focused on the interaction of renal cells with low-density lipoproteins. Relatively little is known of potential metabolism of high-density lipoproteins (HDL) on renal cells However, diverse pathophysiological situations, such as the nephrotic syndrome and acute renal injury, may be associated with an activated renin-angiotensin system as well as altered renal handling of HDL. Therefore, the present study sought to gain insight into the expression of the HDL receptor scavenger receptor class B type I (SR-BI) in cultured renal cells and a potential regulation by angiotensin II (ANG II). Methods. Different renal cells lines and primary cultures (proximal tubular and mesangial cells) were screened by western blot for the expression of SR-BI. MCT cells, a mouse proximal tubular cell line, were selected for further studies. SR-BI protein and mRNA expression were determined after treatment with various doses of ANG II in the presence or absence of AT 1 - or AT 2 -receptor blocker. Uptake of HDL-associated cholesteryl ester into MCT cells was determined. Finally, rats were infused intraperitoneally with ANG II for 3-7 days, proximal tubules were isolated by differential centrifugation and SR-BI protein expression was assessed. Results. SR-BI protein was expressed in various primary cultures and permanent renal cell lines. ANG II (10 -10 -10 -6 M) treatment for 24h induced a significant down-regulation of SR-BI protein and mRNA expression in MCT cells. This suppression was attenuated by an AT 1 -receptor antagonist whereas an AT 2 -blocker was without effect. MCT cells revealed a high selective uptake of HDL cholesteryl ester that was significantly higher than that in syngeneic mesangial cells. ANG II for 24 h significantly reduced this selective HDL cholesteryl ester uptake into MCT, but not mesangial cells. Finally, ANG II- infusion into rats for 3 and 7 days induced a significant decrease of SR-BI protein expression in isolated tubules. Conclusions. Our data show that ANG II mediates down-regulation of SR-BI expression on proximal tubular cells in vivo and in vitro. However, the effects were small and additional experiments are necessary to confirm these first observations. The attenuated SR-BI expression is functionally relevant and associated with a decrease in cholesteryl ester uptake. ANG II-mediated suppression may contribute to various pathophysiological situations, such as acute tubular injury, the nephrotic syndrome and atherosclerosis.

The cause of paraneoplastic membranous nephropathy is unclear. In the current case, new expression of THSD7A in a gallbladder carcinoma and the development of membranous nephropathy may indicate a potential mechanism for the association between cancer and this nephropathy.

Background. The course of glomerulonephritis varies even within the same histological entity, which suggest that genetic factors determine the progression of inflammatory renal diseases. We studied a potential relationship between the C242T gene polymorphism of p22 phox , a subunit of the NAD(P)H oxidase, and frequency as well as progression of immunoglobulin A (IgA) nephropathy. Patients with lupus nephritis were also investigated. The distribution of the C242T gene variation of p22 phox has not been previously studied in patients with renal disease. Methods. Patients with IgA nephropathy were from a homogenous ethnic group of patients living in Northern Germany (ns127). Patients with active lupus nephritis WHO classes IIIuIV (ns46) were also studied. All diagnoses were confirmed by renal biopsy. Healthy blood donors (ns151) exhibited a genotype distribution similar to previously reported values for Caucasians (CC, 41.2%; CT, 45%; TT, 13.8%). However, C242T genotype distribution was not significantly different (x 2 test) in patients with IgA nephropathy (CC, 44.9%; CT, 48%; TT, 7.1%) or in active lupus nephritis (CC, 54.3%; CT, 34.7%; TT, 11%). Grouping of IgA nephropathy patients as those with mild renal impairment at the time of biopsy (serum creatinine -1.3 mgudl) and those with more severe renal failure (serum creatinine )1.3 mgudl) also failed to show a relationship with p22 phox polymorphism. Log-rank analysis for up to 15 years in selected cases of IgA nephropathy did not show a significant difference in renal survival rate among the three genotypes. Conclusions. It appears that the C242T polymorphism is not associated with IgA nephropathy or active lupus nephritis and may not affect the progressive deterioration of renal function in patients with IgA nephropathy. However, whether the C242T polymorphism plays a role in other renal diseases remains to be studied.

Diabetes mellitus type II and arterial hypertension are major risk factors for peripheral arterial disease and have been considered to reduce collateral growth (arteriogenesis). Collateral growth proceeds through different stages. Vascular proliferation and macrophage accumulation are hallmarks of early collateral growth.We here compare the impact of arterial hypertension and diabetes mellitus type II on collateral proliferation (Brdu incorporation) and macrophage accumulation (ED 2 staining) as well as collateral vessel function (collateral conductance) in a rat model of peripheral vascular disease (femoral artery occlusion), diabetes mellitus type II (Zucker fatty diabetic rats and Zucker lean rat controls) and arterial hypertension (induced via clip placement around the right renal arteriy). We furthermore tested the impact of monocyte chemoattractant protein-1 (MCP‑1) on collateral proliferation and macrophage accumulation in these modelsDiabetic animals showed reduced vascular proliferation and macrophage accumulation, which however did not translate into a change of collateral conductance. Hypertensive animals on the contrary had reduced collateral conductances without altered macrophage accumulation and only a marginal reduction in collateral proliferation. Infusion of MCP‑1 only enhanced vascular proliferation in diabetic animals.These findings illustrate that impaired monocyte/macrophage recruitment is responsible for reduced collateral growth under diabetic conditions but not in arterial hypertension suggesting that diabetes mellitus in particular affects early stages of collateral growth whereas hypertension has its impact on later remodeling stages. Successful pro-arteriogenic treatment strategies in a patient population that presents with diabetes mellitus and arterial hypertension need to address different stages of collateral growth and thus different molecular and cellular targets simultaneously.Hintergrund: Diabetes mellitus Typ II und arterieller Hypertonus sind die beiden Hauptrisikofaktoren zur Entwicklung einer peripheren arteriellen Verschlusserkrankung und wurden mit einer Reduktion des Kollateralwachstums (Arteriogenese) in Verbindung gebracht. Das Kollateralwachstum kann in verschieden definierte Stadien eingeteilt werden. Vaskuläre Proliferation und Makrophagen Akkumulation kennzeichnen das frühe Stadium der Kollateralentwicklung. Material und Methoden: In dieser Studie vergleichen wir den Einfluss des arteriellen Hypertonus und des Diabetes mellitus Typ II auf die Gefäßproliferation (BrdU Inkorporation) und Makrophagen Akkumulation (ED2 Färbung) sowie die Funktion der Kollateralgefäße (Kollaterale Konduktanz) in einem Rattenmodel der peripheren arteriellen Verschlusserkrankung, Diabetes mellitus Typ II und arteriellen Hypertonus. Ergebnisse: Diabetische Tiere zeigten eine deutlich reduzierte Gefäßproliferation und Makrophagen Akkumulation, was aber nicht zu einer Änderung der Kollateralen Konduktanz führte. Im Gegensatz dazu zeigten hypertensive Tiere eine deutliche Reduktion der Kollateralen Konduktanz ohne ein Veränderung in der Makrophagen Akkumulation und nur eine geringe Reduktion in der Gefäßproliferation. Die Infusion von Monocyte Chemoatractive Protein 1 führte lediglich zu einer verbesserten Gefäßproliferation in diabetischen Tieren. Schlussfolgerungen: Die verminderte Rekrutierung von Monozyten/Makrophagen ist für das reduzierte Kollateralwachstum unter diabetischen Bedingungen, nicht aber beim arteriellen Hypertonus verantwortlich, was darauf hindeutet, dass insbesondere der Diabetes mellitus das frühe Stadium des Kollateralwachstums negativ beeinflusst, während der arterielle Hypertonus auf spätere Umbauprozesse der Kollateralarterien einwirkt. Erfolgreiche Therapiestrategien zur Verstärkung des Kollateralwachstums müssen in einer Patientenpopulation, die zum großen Teil sowohl einen arteriellen Hypertonus als auch einen Diabetes mellitus aufweist, verschiedene Stadien des Kollateralwachstums berücksichtigen und unterschiedliche zelluläre und molekulare Ziele ansteuern.

Background and objective There are many drugs used in the treatment of hypertension. National and international expert committees regularly publish recommendations for antihypertensive treatment. It is not known how doctors in general practive treat hypertension. Method Questionnaires were sent to 1540 internists, general practitioners and practical doctors in Hamburg, to provide information on their management of hypertensives. There were 458 replies (30%). Results 38% of replying doctors thought that treatment was required if the blood pressure was above 140/90 mmHg, 53% set the level at 160/95 mmHg and 10% above 180/100 mmHg. Internists among them treated hypertension more vigorously than the general practitioners. The most important qualities of a good antihypertensive drug were effective blood pressure reduction (95%), few side effects (83%) and evidence-based reduction of morbidity and mortality (44%). The most frequently used antihypertensives were ACE inhibitors (98%), followed by beta-blockers (86%), diuretics (60%), calcium antagonists (54%) and AT-1 blockers (22%). The most frequently prescribed calcium antagonist was amlodipine (38%), followed by nifedipine preparations (29%), verapamil (18%) and nitrendipine (6%). Diuretics were named as the best tolerated group of antihypertensive drugs, followed by ACE inhibitors, beta-blockers and AT-1-blockers. ACE inhibitors were preferentially used for patients with diabetes mellitus (84%), heart failure (90%) and renal disease (68). Beta-blockers were prescribe for only 72% of patients with coronary heart disease. 212 of doctors did not prescribed new antihypertensives immediately they became available, while 72 used them at once. Conclusion This survey indicates that internists and general practitioners treat hypertensives according to official recommendations and guidelines. But there is a need for further education regarding the definition of normotensive values, and improvement is still possible in the treatment of associated diseases such as diabetes, coronary heart disease and renal disease.

Hintergrund: Hypertensive Schwangerschaftskomplikationen sind eine wichtige Ursache der mutterlichen und fetalen Morbiditat. Hypertensive Erkrankungen in der Schwangerschaft umfassen als ubergeordneter Begriff unterschiedliche Krankheitsbilder von der vorubergehenden Hypertonie mit guter Prognose bis hin zur gefahrlichen Praeklampsie/Eklampsie. Ein Erkennen dieses Krankheitsbildes setzt ein Verstandnis der normalen physiologischen Veranderungen der Schwangerschaft voraus. Pathogenese: Der Praeklampsie/Eklampsie liegt primar ein gestortes Einwachsen der Trophoblastzellen in die uterinen Spiralarterien zugrunde, vermutlich bedingt durch eine gestorte mutterliche Immuntoleranz. Durch eine Endotheldysfunktion kommt es zur uteroplazentaren Minderdurchblutung. Die Balance zwischen Vasokonstriktoren und -dilatatoren ist zugunsten der gefasverengenden Mediatoren verschoben. Die Praeklampsie/Eklampsie ist durch komplexe Storungen im Renin-Angiotensin-System und durch eine Fehlregulation von vasodilatatorischen Substanzen gekennzeichnet. Die Folge ist eine Uberreaktion auf Angiotensin II mit Vasokonstriktion und Hypertonus. Durch eine verminderte Durchblutung der uteroplazentaren Einheit fuhren hypertensive Schwangerschaftserkrankungen und insbesondere die drohende Praeklampsie/Eklampsie zur Wachstumsretardierung des Feten. Das Vollbild der Praeklampsie/Eklampsie ist schlieslich durch eine generalisierte Mikrozirkulationsstorung in Zielorganen wie Gehirn, Leber und Niere gekennzeichnet. Bei einer Leberbeteiligung droht das HELLP-Syndrom. Therapie: Unterschiedlichste Therapien zur Prophylaxe der Praeklampsie/Eklampsie zeigten enttauschende Ergebnisse, sodass auser der Identifizierung von Risikoschwangerschaften, der intensiven Uberwachung und einer Behandlung des Hypertonus zurzeit keine prophylaktischen Masnahmen zur Verfugung stehen. Bei Blutdruckwerten systolisch > 170 mm Hg oder diastolisch > 100 mm Hg sollte eine antihypertensive Therapie begonnen werden. Zur Behandlung des Hypertonus in der Schwangerschaft kommen Medikamente zum Einsatz wie α-Methyldopa und Dihydralazin, die zwar heute als “veraltet” bezeichnet werden, aber in ihrer Wirkung auf den Feten gut charakterisiert sind. ACE-Hemmer und Angiotensin-II-Rezeptor-Antagonisten sind absolut, Diuretika relativ kontraindiziert. Die kausale Therapie der Praeklampsie/Eklampsie ist die Entbindung. Bei Schwangeren vor der 33. Schwangerschaftswoche erfolgen die stationare Aufnahme, Bettruhe, adaquate Blutdruckeinstellung und standige Uberwachung des Feten durch sonographische Fetometrie, Duplexsonographie und Kardiotokographie. Durch diese Masnahmen sind oft eine Schwangerschaftsverlangerung sowie die Induktion der fetalen Lungenreife moglich. Neuere Ergebnisse deuten darauf hin, dass beim sich entwickelnden HELLP-Syndrom die fruhe Gabe von Glucocorticosteroiden zu einer Milderung des Verlaufs fuhren kann. Hypertensive Schwangere, die einer Risikogruppe fur die Entwicklung einer Praeklampsie/Eklampsie angehoren, sollten interdisziplinar in tertiaren Zentren mit entsprechender Erfahrung durch Geburtshelfer, Neonatologen, und Nephrologen betreut werden.

Background. Angiotensin II (ANG II) is a major factor involved in the progression of chronic renal disease, Although the generation of this vasoactive peptide has been investigated in great detail, only a few studies have hitherto addressed the metabolism of ANG II into fragments such as angiotensin III and IV (ANG III, IV) which may exert physiological effects independent of ANG II. Aminopeptidase A (APA) is the major enzyme degrading ANG II. The aim of the current study was to evaluate glomerular APA expression in rats with two-kidney, one-clip hypertension. Methods. The left renal artery was restricted with a 0.2-mm silver clip. Kidneys were harvested 1 and 4 weeks after surgery. APA enzyme and protein expression was evaluated in kidney sections. Total APA enzyme activity and mRNA expression was assessed in isolated glomeruli. Degradation of exogenous ANG II by isolated glomeruli was measured with reverse-phase high-performance liquid chromatography. Results. APA enzyme activity, protein, and mRNA expression were stimulated in the clipped kidney 1 week after surgery compared with the contralateral kidney or normal controls. In contrast, 4 weeks after clipping APA activity and expression was higher in the contralateral kidney. In parallel to these findings, degradation of ANG II was greatest in isolated glomeruli obtained from the clipped kidney after 1 week. However, preparations from the contralateral kidney 4 weeks after surgery were more active in the metabolism of exogenous ANG II. Conclusion. The present study provides evidence that APA is complexly regulated in in vivo situations with an activated local renin-ANG II system. ANG II appears to play a direct role in this regulation. However, since conversion of ANG II to ANG III by APA is the initial step leading to the formation of ANG IV which may exert detrimental effects not mediated through classical ANG II receptors, a local increase in APA activity may contribute to the progression of chronic renal disease even during complete AT 1 -receptor blockade.

Aims/hypothesis. Renal hypertrophy occurs early in diabetes mellitus and precedes the development of glomerulosclerosis and tubulointerstitial fibrosis. We have previously shown that cultured mesangial cells exposed to high glucose are arrested in the G1-phase of the cell cycle and undergo cellular hypertrophy. High glucose-mediated induction of p27Kip1, an inhibitor of cyclin-dependent kinases, is essential in this process. Further investigations have also shown that p27Kip1 and p21Cip1, other cyclin-dependent kinase inhibitors, are up regulated in the kidneys of mice with Type I (insulin-dependent) as well as Type II (non-insulin-dependent) diabetes mellitus. Our study was undertaken to test a potential effect of short-term treatment with the angiotensin-converting enzyme inhibitor enalapril on the glomerular expression of the cyclin-dependent kinase inhibitors p16INK4, p21Cip1, and p27Kip1 in BBdp rats, an autoimmune model of Type I diabetes.¶Methods. We evaluated p16INK4, p21Cip1, and p27Kip1 protein expression in isolated glomeruli by western blots. We also assessed p27Kip1 positive glomerular cells by immunohistochemistry.¶Results. Glomerular expression of all three cyclin-dependent kinase inhibitors were stimulated in BBdp rats compared with non-diabetic BBdr animals. Enalapril treatment for 3 weeks, started after the onset of diabetes, reduced the glomerular expression of p16INK4 and p27Kip1 but not of p21Cip1. Enalapril also prevented the increase in kidney weights observed in BBdp rats but had no effect on systolic blood pressure or glucose concentrations.¶Conclusion/interpretation. Our data show that enalapril attenuates the glomerular expression of cyclin-dependent kinase inhibitors in diabetes and suggest a molecular mechanism of how angiotensin-converting enzyme inhibitors prevent renal hypertrophy in diabetes. [Diabetologia (1999) 42: 1425–1432]

Systemic hypertension is a major risk factor that determines the rate of progression of kidney disease. The underlying mechanisms, however, are incompletely understood. To gain insight into these mechanisms, the present study was undertaken to characterize the effects of renovascular hypertension on the course of anti-thymocyte antibody-induced glomerulonephritis. Glomerulonephritis was induced in rats 6 weeks after the initiation of two-kidney, one-clip hypertension, when blood pressure was already increased. Structure and function of the clipped and the nonclipped kidney were examined 5 days later. Glomerular filtration rate (GFR) was measured by inulin clearance. The induction of nephritis did not alter the blood pressure in either hypertensive rats or normotensive controls. Albuminuria increased slightly in normotensive rats after the induction of nephritis, whereas no significant differences were found between hypertensive rats with or without nephritis. No significant differences were found for the GFR values of normotensive controls and nephritic animals or for values in the clipped kidney with or without nephritis. However, the GFR of the nonclipped kidney was significantly reduced in nephritic animals as compared with all other groups. Morphologic evaluation revealed that hypertensive rats with nephritis exhibited a combination of characteristics of nephritis and hypertensive glomerular injury. Histologic findings of nephritis, such as glomerular binding of rabbit IgG and glomerular proliferation and mesangial matrix expansion, were similar after the induction of nephritis in controls and in the clipped and nonclipped kidneys of hypertensive animals. However, intraglomerular microaneurysms were significantly more often found in the nonclipped kidneys after the induction of nephritis. Hypertension-induced deterioration of glomerular function was not associated with marked morphologic deterioration but rather with a combination of the characteristics of nephritis and hypertensive glomerular injury. (J Lab Clin Med 1999;134:292-303)

Monocyte chemoattractant protein-1 mediates collagen deposition in experimental glomerulonephritis by transforming growth factor-βbgr;. Background Monocyte chemoattractant protein-1 (MCP-1) plays a significant role in the recruitment of monocytes/macrophages in experimental glomerulonephritis (GN). Because recent evidence points to possible profibrogenic effects of leukocyte-derived factors in GN, this study was designed to evaluate the role of the chemokine MCP-1 in the fibrogenesis of experimental GN. Methods Rats with an anti-thy-1–induced GN were treated with a neutralizing antiserum against MCP-1. Glomerular collagen type IV, as a marker of glomerular matrix deposition, was assessed by Northern and Western blotting and immunohistology. Transforming growth factor-βbgr; (TGF-βbgr;), an important mediator of this matrix expansion, was studied by Northern and Western blotting. Results The induction of GN resulted in a significant increase of glomerular collagen type IV deposition and TGF-βbgr; synthesis. The neutralization of MCP-1 significantly reduced the enhanced collagen type IV protein synthesis and deposition without affecting collagen mRNA expression. However, both the enhanced transcription and protein synthesis of TGF-βbgr; were inhibited by anti–MCP-1 antiserum in nephritic animals. Conclusions In this model of GN, MCP-1 has a fibrogenic effect through the stimulation of TGF-βbgr;. MCP-1 is thus not only important for the recruitment of inflammatory cells, but also mediates glomerular matrix accumulation.

Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: Evidence for an involvement of protein kinase C. Background Angiotensin II infusion has been shown to cause hypertension and endothelial dysfunction and to increase superoxide (O -· 2 ) production in vascular tissue, mainly via an activation of nicotinamide adenine dinucleotide (phosphate) [NAD(P)H]-dependent oxidase, the most significant O -· 2 source in endothelial and/or smooth muscle cells. With these studies, we sought to determine whether endothelial dysfunction in renovascular hypertension is secondary to an activation of these oxidases. Methods Endothelial function in aortas from rats with two kidney-one clip (2K-1C) hypertension and age-matched controls was assessed using isometric tension studies in organ chambers. Changes in vascular O -· 2 production were measured using lucigenin-enhanced chemiluminescence and electron spin resonance spectroscopy. Results In hypertensive animals, relaxation to endothelium-dependent (acetylcholine) and endothelium-independent nitrovasodilators (nitroglycerin) was impaired. Constriction to a direct activator of protein kinase C (PKC) phorbol ester 12,13 dibutyrate (PDBu) was enhanced, and vascular O -· 2 was significantly increased compared with controls. Vascular O -· 2 was normalized by the PKC inhibitor calphostin C, by the inhibitor of flavin-dependent oxidases, diphenylene iodonium, and recombinant heparin-binding superoxide dismutase, whereas inhibitors of the xanthine oxidase (oxypurinol), nitric oxide synthase (N G -nitro-L-arginine) and mitochondrial NADH dehydrogenase (rotenone) were ineffective. Studies of vascular homogenates demonstrated that the major source of O -· 2 was a NAD(P)H-dependent oxidase. Incubation of intact tissue with PDBu markedly increased O -· 2 , the increase being significantly stronger in vessels from hypertensive animals as compared with vessels from controls. Endothelial dysfunction was improved by preincubation of vascular tissue with superoxide dismutase and calphostin C. Conclusions We therefore conclude that renovascular hypertension in 2K-1C rats is associated with increased vascular O -· 2 leading to impaired vasodilator responses to endogenous and exogenous nitrovasodilators. Increased vascular O -· 2 is likely secondary to a PKC-mediated activation of a membrane-associated NAD(P)H-dependent oxidase.

Previous studies have demonstrated that angiotensin II stimulates expression of transforming growth factor-beta (TGF-beta) in cultured renal cells. To investigate whether similar mechanisms are operative in vivo, glomerular TGF-beta mRNA expression was investigated in two-kidney, one-clip (2-K 1-C) hypertensive rats. Glomerular TGF-beta1 transcripts were elevated in the clipped kidney 6 d, but not 3 d, after surgery. Later, during the course of the disease (21 to 35 d), TGF-beta1 mRNA was upregulated in contralateral kidneys compared with sham-operated control kidneys. There was no difference in plasma TGF-beta1 levels between 2-K 1-C rats and controls. Treatment with the AT1 receptor antagonist losartan, as well as with triple therapy (hydralazine, reserpine, and hydrochlorothiazide), started 1 d after clipping, significantly reduced systolic BP in hypertensive rats at day 21 after clipping. Both treatments were equally effective in preventing the increase in glomerular TGF-beta1 mRNA and protein expression in the contralateral kidney at day 21. In a second set of experiments, interventional treatment with losartan or triple therapy, starting 14 d after surgery, was investigated. This treatment for 3 wk significantly reduced the increase in TGF-beta1 expression in the contralateral kidney. At day 35 after clipping, considerable glomerular damage and sclerosis were present, mainly in contralateral kidneys. Interventional treatment with losartan or triple therapy partly prevented this glomerular damage of the contralateral kidney. The data demonstrate that TGF-beta1 expression in the contralateral kidney in 2-K 1-C rats is regulated by the increase in systemic BP rather than by direct effects of angiotensin II.

Patients with chronic kidney failure commonly are advised to maintain a generous fluid intake. The reason that physicians tend to recommend such an increased fluid intake is difficult to understand. A scientific basis does not exist. To the modern nephrologist, this element of the therapeutic armamentarium seems long to be outdated; however, it was once recommended by authorities (1) and is still being advocated by primary care physicians. “My wife forgot to ask whether it is really necessary to keep a fluid intake of 4.5 L daily. This was the advice of her primary care physician. Perhaps 3 L would be better for her BP and sufficient for her kidney.” The husband of the patient raised this question at the end of her consultation visit at our University Hospital Clinic. The patient was seen for a second opinion regarding the management of her chronic kidney disease (CKD) manifested by a serum creatinine of 3.0 mg/dl and non-nephrotic proteinuria. The husband, who is an oncologist, was mainly concerned because his wife was losing sleep at night because of her many nocturnal trips to the bathroom. If the oncologist and his wife were an isolated case, then we would not be writing this article. However, over the years, we have encountered numerous such examples in our nephrology consultative practice. We suggest further that the patients who have CKD and complain about the instruction to drink large amounts of fluid may represent only the “tip of the iceberg.” Likely, there are many more patients who have CKD and whom we nephrologists never hear about because they silently accept their watery fate. Without complaint, they follow the advice of their primary care physician, which is reinforced by the lay press (“drink at least 8 glasses of water a day”) and by well-meaning friends who …

T cells participate in angiotensin II (Ang II)–induced hypertension. However, the specific subsets of T cells that are important in the end-organ damage are unknown. T-helper 17 cells are a recently identified subset that produces interleukin 17 (IL-17) and requires interleukin 23 (IL-23) for expansion. To evaluate the role of the T-helper 17 immune response in hypertensive renal and cardiac end-organ damage, hypertension was induced with deoxycorticosterone acetate (DOCA)+Ang II in wild-type (n=39) and IL-17–deficient (n=31) mice. The injury was evaluated at day 4 and day 14. To inactivate the IL-17/IL-23 axis at a different point, DOCA+Ang II hypertension was also induced in IL-23p19–deficient mice. Renal infiltration by T-helper 17 cells was increased in hypertensive wild-type mice. Systolic blood pressure did not differ between hypertensive IL-17–deficient and wild-type mice. Three days after induction of hypertension, a significantly higher albuminuria was found in IL-17–deficient than in wild-type mice (196±64 versus 58±16 mg/mg albumin/creatinine). Histology revealed significantly more glomerular injury (1.04±0.06 versus 0.67±0.05) and renal infiltration of γδ T cells in IL-17–deficient than in wild-type mice after 14 days. Similarly, significantly higher albuminuria, glomerular injury, and γδ T cell infiltration were found in IL-23p19–deficient mice with DOCA+Ang II–induced hypertension. DOCA+Ang II also induced cardiac damage as assessed by heart weight, cardiac fibrosis, as well as expression of fetal genes and matrix components, but no significant differences were found among IL-17 –/– , IL-23p19 –/– , and wild-type mice. IL-17/IL-23 deficiency accelerates DOCA+Ang II–induced albuminuria and hypertensive renal but not cardiac end-organ damage.

Purpose: In 2011 a nationwide outbreak of Shiga toxin-producing E. coli (STEC) O104:H4 infection occurred in Germany with severe hemorrhagic colitis and hemolytic-uremic syndrome (HUS). We defined abdominal radiologic findings in these patients and correlated them with clinical parameters. Materials and Methods: 23 patients (7 men; age: 48 ± 19 years) with O104:H4 colitis and/or HUS received abdominal CT (n = 12) or radiographs (n = 11). Colonic distension, air-fluid levels, and free intraabdominal air were assessed. Colonic wall thickening, contrast enhancement, pericolic stranding, and ascites were evaluated on CT. Laboratory parameters and clinical presentation were reviewed. Chi-square test, Student’s t-test, McNemar’s test and Spearman correlation were performed. Results: Colonic lumen distension was seen in 16/23 patients (69.6 %). The ascending colon (11/23 patients; 47.8 %) and transverse colon (12/23 patients; 52.2 %) were dilated significantly more often (p = 0.006 and p = 0.003, respectively) than the descending colon (1/23; 4.3 %). All 12 patients undergoing CT scanning had abnormally thickened colonic wall segments, 3 (25 %) had pancolic involvement and 9 (75 %) had segmental involvement. The descending colon was predominantly affected (11/12 patients; 91.7 %) and thickened significantly more often than other colonic segments (p Conclusion: The segmental type of STEC O104:H4 colitis mainly affects the descending colon with upstream distension of the transverse/ascending colon and differs from other types of colitis.

Obesity is an increasingly observed pathologic entity in the industrialized world and causally linked to the development of hypertension. Consequently, not only the prevalence of obesity but also the prevalence of obesity hypertension is increasing worldwide. In the context of antihypertensive treatment, data from clinical trials indicate that all first-line antihypertensive drugs possess a similar efficacy in reducing systemic blood pressure and hypertension-related end-organ damage in obese hypertensive subjects. Nevertheless, some antihypertensive agents, such as β-blockers or thiazide diuretics, may have unwanted side effects on the metabolic and hemodynamic abnormalities that occur in both obesity and hypertension. However, current guidelines still do not include recommendations for state-of-the-art treatment of obese patients with hypertension. Hence, the aim of this article is to provide recommendations for the appropriate use of antihypertensive agents in obese patients mostly based on personal expertise and pathophysiologic assumptions. For instance, thiazide diuretics and β-blockers are reported to reduce insulin sensitivity and (at least transiently) increase triglyceride and low-density lipoprotein cholesterol levels, whereas calcium channel blockers are metabolically neutral and angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and renin inhibition may increase insulin sensitivity. The renin-angiotensin-aldosterone system in the adipose tissue has been implicated in the development of arterial hypertension and sodium retention plays a central role in the development of obesity-related hypertension. Therefore, treatment with a blocker of the renin-angiotensin-aldosterone-system and a thiazide diuretic should be considered as first-line antihypertensive drug therapy in obesity hypertension.

e read with great interest the recent articleby Gosse et al. [1]. Compliance is a frequentproblem during the treatment of resistant hyper-tension. Simple tools are needed to give physicians theopportunity to evaluate compliance and adherence, forexample, in patients with resistant hypertension. Theseauthors suggested that concomitantly measuring plasmarenin activity (PRA) and plasma renin concentration(PRC) may serve as a simple tool to appreciate regularintake of the direct renin inhibitor aliskiren. Aliskiren is theonly antihypertensive drug that increases renin concen-tration and at the same time decreases renin activity. Theauthors simultaneously measured PRA and PRC in patientswho had either received aliskiren or other treatments. Ahigh PRC/PRA ratio reliably showed whether patients hadtaken aliskiren or not. Although at first glance elegant andinteresting, this approach has three major problems, whichwe would like to mention:1. Measuringreninactivityandconcentrationisexpens-ive and complicated, as the PRC sample has to behandled at room temperature and the PRA sample at4

Suppression of angiotensin II formation by angiotensin-converting enzyme inhibitors or blockade of the angiotensin II receptor by angiotensin receptor blockers is a powerful therapeutic strategy to slow the progression of renal disease. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers provide only imperfect protection against the progression of chronic kidney disease to end-stage renal failure. Hence, innovative approaches are needed to keep patients with chronic kidney disease off dialysis. Angiotensin II activates at least two receptors, namely the angiotensin II type 1 (AT 1) and angiotensin II type 2 (AT2) receptors. The majority of the effects of angiotensin II, such as vasoconstriction, inflammation, and matrix deposition, are mediated via the AT1 receptor. It is thought that the AT2 receptor counteracts these effects and plays a role in nephroprotection. However, recent data support the notion that the AT2 receptor transduces pro-inflammatory effects and promotes fibrosis and hypertrophy. Therefore, the question of whether stimulation of the AT2 receptor could represent a silver bullet for the treatment of chronic kidney disease or may, on the contrary, exert detrimental effects on renal physiology remains unresolved. Recent data from AT2 receptor-knockout mice demonstrate that the loss of AT2 receptor signalling is associated with increased renal injury and mortality in chronic kidney disease. This raises the expectation that pharmacological stimulation of the AT2 receptor may positively influence renal pathologies. However, further research is needed to explore the question whether AT2 receptor stimulation may represent a new therapeutic strategy for the treatment of chronic kidney disease.

Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation1. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.

Obesity prevalence is increasing. Obesity frequently coexists with-and can cause or worsen-arterial hypertension. However, no current guidelines provide specific recommendations. Antihypertensive drug treatment is indicated in most obese hypertensive patients, leading to the obvious question: what is the best drug treatment for this population? Some antihypertensive agents may have unwanted effects on the metabolic and hemodynamic abnormalities linking obesity and hypertension. Without adequate studies, recommendations for or against each class of antihypertensive agents are based on subjective criteria and pathophysiologic assumptions. Diuretics and beta-blockers have unwanted effects, whereas calcium antagonists are metabolically neutral, and angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers may increase insulin sensitivity. The renin-angiotensin system in adipose tissue has been implicated in arterial hypertension, and sodium retention is central to obesity-related hypertension. Therefore, an ACE inhibitor or diuretic should be considered as first-line antihypertensive drug therapy in obesity-hypertension.