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Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by hemodynamic injury. Inflammation also plays an important role in the pathophysiology and contributes to the deleterious consequences of this disease. Cells of the innate immune system including monocyte/macrophages and dendritic cells can promote blood pressure elevation via effects mostly on kidney and vascular function. Moreover, convincing evidence shows that T and B cells from the adaptive immune system are involved in hypertension and hypertensive end-organ damage. Skin monocyte/macrophages, regulatory T cells, natural killer T cells, and myeloid-derived suppressor cells have been shown to exert blood pressure controlling effects. Sodium intake is undoubtedly indispensable for normal body function but can be detrimental when taken in excess of dietary requirements. Sodium levels also modulate the function of monocyte/macrophages, dendritic cells, and different T cell subsets. Some of these effects are mediated by changes in the microbiome and metabolome that can be found after high salt intake. Modulation of the immune response can reduce severity of blood pressure elevation and hypertensive end-organ damage in several animal models. The purpose of this review is to briefly summarize recent advances in immunity and hypertension as well as hypertensive end-organ damage.

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.

Arterial hypertension affects about one third of the German population with a prevalence increasing with age up to 60 %. Globally, more than a quarter gedoppelt of the population are considered hypertensive, resulting in a total of more than one billion people. Not only due to such high prevalence, but also because of its multiple cardiovascular, renal, ocular, and cognitive complications, arterial hypertension is a leading contributor to the global burden of disease and responsible for up to 10 million deaths worldwide. Contrary to the great importance of arterial hypertension resulting from such high prevalence and immense impact on health worldwide, awareness of disease is low in affected people. Less than every second patient knows about his or her disease status and less than 40 % of patients in Europe show adequate blood pressure control with a treatment target of 140/90 mmHg despite antihypertensive treatment. This overview of arterial hypertension, its etiology, diagnostic tools, and therapeutic options aims to improve the understanding of arterial hypertension and to facilitate the diagnostic and therapeutic approach, eventually resulting in a better and more successful handling of patients with arterial hypertension.

Previous studies demonstrated an association between severe chronic periodontitis (CP) and metabolic syndrome (MetS). However, these studies mostly used the outdated National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) III case definition of MetS. Additionally, CP was rarely diagnosed based on a full-mouth examination. Thus, the aim of the current study was to re-evaluate the potential association between CP and MetS in the Hamburg City Health Study (HCHS), a large population-based survey of middle-aged and elderly men and women in Germany, in view of more current definitions of MetS and CP.A cross-sectional study was performed with baseline-data from participants of the HCHS. Periodontitis severity grades were determined in a random sample of 6,209 participants of which 5,456 had sufficient data to call absence or presence of MetS. Variables defining MetS according to the currently valid harmonized definition were determined and a full-mouth examination was performed, including determination of the clinical attachment loss, bleeding on probing, and dental plaque index. CP was classified in three grades of severity (none/mild, moderate, and severe). The Kruskal-Wallis test or the Chi-squared test were used for descriptive statistics and multivariate logistic regression models with and without adjustments for potential confounders (age, sex, smoking, high-sensitivity C-reactive protein [hsCRP], energy intake, and physical activity) were used to test for associations.The prevalence of MetS (39.0%) increased according to the severity grades of periodontitis (none/mild: 33.6%; moderate: 38.7%, and severe: 46.8%). Multivariate logistic regression analyses demonstrated that severe but not moderate CP was associated with MetS after adjusting for age and sex (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03 to 1.48; P = 0.02). However, the association was attenuated after additional adjustment for smoking (OR, 1.19; 95% CI, 0.99 to 1.43; P = 0.058) and hsCRP, energy intake, and physical activity (OR, 1.11; 95% CI, 0.91 to 1.36; P = 0.294).The use of the more current definitions for MetS and CP confirmed previous observations of an age- and sex-adjusted association between severe CP and MetS. Smoking, high-energy intake, and low physical activity were identified as important lifestyle-related confounders. Abdominal obesity, as indicated by elevated waist circumference, was determined as the most important component of MetS in relationship to CP.

Aim Aim of this study was to investigate the association between periodontitis and arterial hypertension, both of which show correlations with classical cardiovascular risk factors and inflammatory activity. Materials and methods A cross-sectional analysis of data from a large population-based health survey (the Hamburg City Health Study, HCHS) including 5934 participants with complete periodontal examination and blood pressure data, of whom 5735 had medical records regarding anti-hypertensive medication, was performed. Probing depths, gingival recessions, bleeding on probing (BOP), dental plaque, and decayed-missing-filled teeth (DMFT) indices were recorded as measures of oral health. Clinical attachment loss (CAL) per tooth was calculated and periodontitis was staged into three groups (no/mild, moderate, severe). Arterial hypertension was diagnosed based on the participants’ medication history and systolic and diastolic blood pressure values. Logistic regression models were constructed accounting for a set of potential confounders (age, sex, smoking, body mass index (BMI), diabetes, educational level, alcohol intake) and high sensitivity-C-reactive protein (hsCRP). Results The odds of arterial hypertension increased significantly along with periodontitis severity (OR for severe periodontitis: 2.19; 95% CI 1.85–2.59; p p p = 0.02; OR for moderate PD: 1.30, 95% CI 1.11–1.52, p = 0.001). The fraction of participants with undertreated hypertension (untreated and poorly controlled hypertension) was considerably larger in participants with severe periodontitis than in those with no/mild periodontitis (50.1% vs. 37.4% for no/mild periodontitis). Conclusions The study shows an association between periodontitis and arterial hypertension that is independent of age, sex, diabetes, BMI, smoking, educational level, and alcohol intake. In addition, undertreatment of hypertension was more common in people with severe periodontitis compared with periodontally more healthy people.

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.

Increasing evidence indicates that hypertension and hypertensive end organ damage are not only mediated by haemodynamic injury but that inflammation also plays an important role. The complement system protects the host from a hostile microbial environment and maintains tissue and cell integrity through the elimination of altered or dead cells. As an important effector arm of innate immunity, it plays also central roles in the regulation of adaptive immunity. Thus, complement activation may drive the pathology of hypertension through its effects on innate and adaptive immune responses, aside from direct effects on the vasculature. Recent experimental data strongly support a role for complement in all stages of arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical haemolytic uraemic syndrome suggest also a role for complement in the development of malignant nephrosclerosis. Here, we review the role of complement in hypertension and hypertensive end organ damage. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.

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.

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a major deubiquitinating enzyme of the nervous system and associated with the development of neurodegenerative diseases. We have previously shown that UCH-L1 is found in tubular and parietal cells of the kidney and is expressed de novo in injured podocytes. Since the role of UCH-L1 in the kidney is unknown we generated mice with a constitutive UCH-L1-deficiency to determine its role in renal health and disease. UCH-L1-deficient mice developed proteinuria, without gross changes in glomerular morphology. Tubular cells, endothelial cells, and podocytes showed signs of stress with an accumulation of oxidative-modified and polyubiquitinated proteins. Mechanistically, abnormal protein accumulation resulted from an altered proteasome abundance leading to decreased proteasomal activity, a finding exaggerated after induction of anti-podocyte nephritis. UCH-L1-deficient mice exhibited an exacerbated course of disease with increased tubulointerstitial and glomerular damage, acute renal failure, and death, the latter most likely a result of general neurologic impairment. Thus, UCH-L1 is required for regulated protein degradation in the kidney by controlling proteasome abundance. Altered proteasome abundance renders renal cells, particularly podocytes and endothelial cells, susceptible to injury.

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

Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g−1·min−1) and salt in wild-type ( n = 34) and C5aR1-deficient mice ( n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension.

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

Traditionally, arterial hypertension and subsequent end‐organ damage have been attributed to haemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign microorganisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Over the past few years, important findings have revolutionized hypertension research. Firstly, in 2007, a seminal paper showed that adaptive immunity is involved in the pathogenesis of hypertension. Secondly, salt storage in the skin and its consequences for cardiovascular physiology were discovered. Thirdly, after the discovery that salt promotes the differentiation of CD4(+) T cells into T(H)17 cells, it was demonstrated that salt directly changes several cells of the innate and adaptive immune system and aggravates autoimmune disease but may improve antimicrobial defence. Herein, we will review pathways of activation of immune cells by salt in hypertension as the framework for understanding the multiple roles of salt and immunity in arterial hypertension and autoimmune disease. 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.

The self-amplifying cascade of messenger and effector molecules of the complement system serves as a powerful danger-sensing system that protects the host from a hostile microbial environment, while maintaining proper tissue and organ function through effective clearance of altered or dying cells. As an important effector arm of innate immunity, it also plays important roles in the regulation of adaptive immunity. Innate and adaptive immune responses have been identified as crucial players in the pathogenesis of arterial hypertension and hypertensive end organ damage. In line with this view, complement activation may drive the pathology of hypertension and hypertensive injury through its impact on innate and adaptive immune responses. It is well known that complement activation can cause tissue inflammation and injury and complement-inhibitory drugs are effective treatments for several inflammatory diseases. In addition to these proinflammatory properties, complement cleavage fragments of C3 and C5 can exert anti-inflammatory effects that dampen the inflammatory response to injury. Recent experimental data strongly support a role for complement in arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical hemolytic uremic syndrome, which is driven by complement activation, suggest a role for complement also in the development of malignant nephrosclerosis. Herein, we will review canonical and noncanonical pathways of complement activation as the framework to understand the multiple roles of complement in arterial hypertension and hypertensive end organ damage.

Opportunistic infections are a major concern in renal and transplant medicine. We present the case of a renal transplant recipient with a generalised Mycobacterium haemophilum infection after an increase in immunosuppressive therapy and treatment with a tumour necrosis factor-α (TNF-α) inhibitor. Infection involved skin and soft tissue, joints and bones, as well as the renal transplant with an interstitial nephritis. Rapid diagnosis using PCR and DNA sequencing allowed early appropriate treatment. Triple antibiotic therapy and reduction in immunosuppression resulted in a slow but sustained recovery. Immunosuppression causes severe opportunistic infections. TNF-α inhibitors are very effective and well tolerated but have an increased susceptibility to infections with mycobacteria. Mycobacterial infections represent a significant clinical risk to transplant recipients because of their aggressive clinical course and the need for complex toxic antibiotic treatments. In these patients, M. haemophilum is a cause of skin infections.

Summary Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis. Depletion of intestinal Th17 cells in germ-free and antibiotic-treated mice ameliorated renal disease, whereas expansion of these cells upon Citrobacter rodentium infection exacerbated pathology. Thus, in some autoimmune settings, intestinal Th17 cells migrate into target organs, where they contribute to pathology. Targeting the intestinal Th17 cell “reservoir” may present a therapeutic strategy for these autoimmune disorders., Graphical Abstract, Highlights • Pathogenic TH17 cells migrate from the gut to the kidney in autoimmunity • TH17 cells egress the intestine in a S1PR1-dependent manner in glomerulonephritis • Targeting microbiota-induced TH17 cells ameliorates extraintestinal TH17 responses, By photolabelling intestinal cells, Krebs and colleagues provide direct evidence that microbiota-induced TH17 cells egress from the gut S1PR1-dependently and infiltrate the kidney via CCL20/CCR6 in immune-mediated diseases. This finding will build the basis for therapies targeting the intestinal TH17 cell “reservoir” to treat extraintestinal TH17 autoimmunity.

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.