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Abstract In malignant hypertension, far more severe kidney injury occurs than in the “benign” form of the disease. The role of high blood pressure and the renin–angiotensin–aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p Key messages The most severe hypertension-induced kidney injury occurs in malignant hypertension. In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades. Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.

Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1–4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p p

Background: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). Methods: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. Results: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. Conclusion: The prominent function of increased RSNA – retaining salt and water – could no longer be observed after renal Ang II receptor blockade in CHF rats.

BACKGROUND Interleukin-11 (IL-11) is a pleiotropic cytokine of the interleukin-6 family. Recent studies revealed its crucial role in the development of cardiovascular fibrosis. In this study we examined IL-11 expression levels in the heart and the kidney exposed to high blood pressure in renovascular hypertensive rats and their correlations to fibrotic markers and kidney injury. METHODS Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats. IL-11 expression was measured by real-time polymerase chain reaction in the left ventricle and the right kidney. The correlation of cardiac IL-11 expression with biomarkers of renal fibrosis was assessed. We further investigated IL-11 expression in 2K1C rats grouped into rats with malignant vs. nonmalignant hypertension (distinguishing criteria: weight loss, number of fibrinoid necrosis, and onion skin lesions). RESULTS Thirty-five days after clipping, mean arterial pressure was significantly increased in 2K1C. Renal IL-11 expression was elevated in 2K1C. In the heart there was only a trend toward higher IL-11 expression in 2K1C. IL-11 in the kidney in 2K1C correlated with the expression of transforming growth factor (TGF)-β1/2, collagens, fibronectin, osteopontin, as well as tissue inhibitors of metalloprotease 1/2. There were also correlations of IL-11 with tissue collagen expansion, number of activated fibroblasts and serum creatinine, but no correlation with mean arterial pressure. Renal expression of IL-11 was highest in rats with malignant hypertension. CONCLUSIONS Renal IL-11 expression of renovascular hypertensive rats is markedly increased and correlates with profibrotic markers and loss of function and might therefore serve as a biomarker for the severity of hypertensive nephrosclerosis.

Aim We have reported earlier that a high salt intake triggered an aestivation‐like natriuretic‐ureotelic body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure. Methods In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24‐hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomics and selected enzyme activity measurements, body Na+, K+ and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra‐arterial blood pressure. Results 5/6 Nx rats were polyuric, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, elevated norepinephrine and copeptin levels with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic‐metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein. Conclusion Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under‐studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.

Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm2) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8–37reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.

We demonstrated earlier that renal afferent pathways combine very likely “classical” neural signal transduction to the central nervous system and a substance P (SP)–dependent mechanism to control sympathetic activity. SP content of afferent sensory neurons is known to mediate neurogenic inflammation upon release. We tested the hypothesis that alterations in SP-dependent mechanisms of renal innervation contribute to experimental nephritis. Nephritis was induced by OX-7 antibodies in rats, 6 days later instrumented for recording of blood pressure (BP), heart rate (HR), drug administration, and intrarenal administration (IRA) of the TRPV1 agonist capsaicin to stimulate afferent renal nerve pathways containing SP and electrodes for renal sympathetic nerve activity (RSNA). The presence of the SP receptor NK-1 on renal immune cells was assessed by FACS. IRA capsaicin decreased RSNA from 62.4 ± 5.1 to 21.6 ± 1.5 mV s (*p + dendritic cells (DCs). An enhanced frequency of CD11c+NK1R+ cell, NK-1 receptor+ macrophages, and DCs was assessed in nephritis. Administration of the NK-1R antagonist aprepitant during nephritis reduced CD11c+NK1R+ cells, macrophage infiltration, renal expression of chemokines, and markers of sclerosis. Hence, SP promoted renal inflammation by weakening sympathoinhibitory mechanisms, while at the same time, substance SP released intrarenally from afferent nerve fibers aggravated immunological processes i.e. by the recruitment of DCs.

End stage chronic kidney disease (CKD) requiring renal replacement therapy is related to poor quality of life and high mortality. Thus, slowing the progression of CKD is an important purpose of therapy. Some general therapeutic approaches aim to slow the decline of renal function and they can be applied in all patients with CKD – irrespective of the underlying cause of CKD. A key intervention is lowering blood pressure (target: ≤ 140/90 mmHg, and in patients with albuminuria ≤ 130/80 mmHg). Inhibitors of the renin angiotensin system preferentially should be used in case of albuminuria, depending on the diabetic status and the level of albuminuria: in diabetics with albuminuria ≥ 30 mg/d, in non-diabetics with albuminuria > 300 mg/d. Mineralocorticoid receptor blockers and endothelin receptors blockers promise novel anti-proteinuric strategies – but still validation of their positive effects on retarding CKD progression is necessary. In patients with diabetic kidney disease, glycemic control aiming for an HbA1c of ≈ 7.0 % has been established to slow CKD progression. Furthermore, SGLT-2 inhibition with empagliflozin may be considered as a new therapeutic approach that provides additional cardiovascular and renal protection. Finally, recent studies suggest: correction of metabolic acidosis and avoidance of episodes of acute renal failure may provide protection against the progression of CKD.

While patients with chronic kidney disease (CKD) have a high prevalence of classical coronary risk factors, there is increasing evidence that atherosclerosis is different in renal compared to nonrenal patients. Therefore, the present study compares changes in different vessels obtained at cardiac surgery between patients with early and advanced CKD and nonrenal control patients.Fifty patients undergoing cardiac bypass surgery were divided into three groups: (i) 24 control patients with creatinine1.3mg/dl, (ii) 14 patients with early CKD (creatinine 1.3-2.0mg/dl), and (iii) 12 patients with advanced CKD (creatinine2.0mg/dl). Aorta, arteria mammaria interna, and vena saphena (V. saphena) were analyzed using morphometry, Kossa stain for vascular calcification, and immunohistochemistry for markers of inflammation and proosteogenic differentiation of vascular smooth muscle cells (VSMCs). Thereby, aortic wall thickness and calcification score of aortic intima and of V. saphena were significantly higher in advanced CKD patients than in nonrenal control patients, whereas significant vascular inflammation and proosteogenic dedifferentiation of VSMC and calcification of the aortic media were already present in early CKD. Interestingly, marked calcification of the V. saphena magna was seen in advanced CKD. Of note, calcium-phosphate product correlated well with markers of inflammation, but not with calcification itself.Early stages of CKD are already associated with local up-regulation of proinflammatory and proosteogenic molecules in the vascular wall and calcification of the aortic media. These findings point to the importance of local microinflammation in CKD and may shed new light on the potentially overestimated role of the calcium-phosphate product for vessel calcification.

Chronic renal failure leads to muscle mass loss and hypertension, which according to textbook teaching occur secondary to an inability of the kidneys to excrete solutes and water. We found instead that rats with experimental chronic renal failure constantly lost body water, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy that relies on complex physiologic-metabolic adjustment across multiple organs to prevent otherwise lethal dehydration. We show that rats with chronic renal failure utilize these ancient water conservation motifs to successfully stabilize their body water. Metabolic aestivation responses to chronic renal failure require nitrogen-rich organic osmolyte production. Continuous endogenous energy and nitrogen supply from skeletal muscle in support of this metabolic requirement explains “renal” muscle mass loss. Accompanying circulatory aestivation responses are designed to limit skin water loss. This process requires vasoconstriction, which explains “renal” hypertension.

Transplant centers now accept living donors with well-controlled hypertension. Little is known whether hypertension in living donors affects recipient's kidney function. We aimed to examine potential differences in kidneys from hypertensive donors compared to normotensive donors with respect to renal function over 36 months and histologic findings at transplantation (T0) and 12 months after transplantation (T1). Retrospective single-center analysis of 174 living donor-recipient pairs (age > 18; transplantation date 1/2008-3/2016). Hypertension in donors was defined as being on antihypertensive medication. All biopsies were assessed by the same blinded, experienced renal pathologist. Biopsies were scored for glomerulosclerosis, IFTA, and arteriosclerosis. Regression models were used to examine the relationship of donor hypertension with renal function and histologic changes. Hypertensive donors were significantly older than normotensive donors. Chronic changes such as tubular atrophy and atherosclerosis were more evident in kidneys from hypertensive donors at T0 as well as T1. Donor hypertension was independently associated with histologic changes at T0 and T1 but not with renal function over the follow period. Despite more pronounced histologic changes in kidneys from hypertensive living donors, these grafts exhibited a similar functional outcome. However, they subsequently might be at a greater risk and warrant thorough follow-up care.

Objective ICG fluorescence angiography enables a quantitative real-time perfusion assessment in kidney transplantation. The results of intraoperative microperfusion of the kidney allograft were compared to the renal chronicity score in pre-transplantation kidney biopsy specimens. The intrarenal resistance index was calculated by duplex sonography as a method of reference. Methods Seventy-seven patients with end-stage renal disease undergoing kidney transplantation were prospectively included in two centers. Correlation analysis of chronic changes in kidney biopsy specimens and the IN of ICG fluorescence signal were investigated. Results The results yielded a significantly negative correlation for the renal chronicity (r = -0.294, P = 0.017) as well as the intestinal fibrosis and tubular atrophy score (r = -0.328, P = 0.007). There was a significant inverse relationship between the IN and the mean RI values of the upper pole of the kidney allograft. Conclusions In summary, fluorescence angiography reflects preexisting morphological changes of the renal cortex. ICG angiography may serve as an alternative method for the assessment of microperfusion of the kidney allograft.

Integrins play an important role in vascular biology. The α8 integrin chain attenuates smooth muscle cell migration but its functional role in the development of atherosclerosis is unclear. Therefore, we studied the contribution of α8 integrin to atherosclerosis and vascular remodelling. We hypothesized that α8 integrin expression is reduced in atherosclerotic lesions, and that its under-expression leads to a more severe course of atherosclerosis. α8 Integrin was detected by immunohistochemistry and qPCR and α8 integrin-deficient mice were used to induce two models of atherosclerotic lesions. First, ligation of the carotid artery led to medial thickening and neointima formation, which was quantified in carotid cross-sections. Second, after crossing into ApoE-deficient mice, the formation of advanced vascular lesions with atherosclerotic plaques was quantified in aortic en face preparations stained with Sudan IV. Parameters of renal physiology and histopathology were assessed: α8 integrin was detected in the media of human and murine vascular tissue and was down-regulated in arteries with advanced atherosclerotic lesions. In α8 integrin-deficient mice (α8(-/-) ) as well as α8(+/-) and α8(+/+) littermates, carotid artery ligation increased media:lumen ratios in all genotypes, with higher values in ligated α8(-/-) and α8(+/-) compared to ligated α8(+/+) animals. Carotid artery ligation increased smooth muscle cell number in the media of α8(+/+) mice and, more prominently, of α8(-/-) or α8(+/-) mice. On an ApoE(-/-) background, α8(+/-) and α8(-/-) mice developed more atherosclerotic plaques than α8(+/+) mice. α8 Integrin expression was reduced in α8(+/-) animals. Renal damage with increased serum creatinine and glomerulosclerosis was detected in α8(-/-) mice only. Thus, under-expression of α8 integrin aggravates vascular lesions, while a complete loss of α8 integrin results in reduced renal mass and additional renal disease in the presence of generalized atherosclerosis. Our data support the hypothesis that integrin α8β1 has a protective role in arterial remodelling and atherosclerosis.

Objective Sufficient blood supply is a crucial factor determining postoperative allograft function in kidney transplantation. Therefore, besides the surgeon's individual impression, a method for evaluating the quality of the organ's microperfusion is required. Laser fluorescence angiography with indocyanine green (ICG) is an emerging tool for this purpose. However, no reproducible quantification of ICG fluorescence has been performed in transplantation so far. Methods This retrospective two-center study was designed to evaluate the dosing of ICG for intraoperative laser fluorescence angiography in kidney transplantation. The Spy Elite® system (NOVADAQ, Canada) was employed for quantitative assessment of allograft microperfusion. ICG was administered systemically 5 minutes after reperfusion applying doses between 0.25 and 0.01 mg ICG per kg body weight. Quantitative assessment was performed with the implemented SPY-Q Software. Results A total of 57 kidney recipients were included in two centers. The generated curves showing ICG IN and EgR were not evaluable due to oversensing when doses exceeded 0.02 mg per kg body weight. Conclusions Fluorescence angiography with ICG is an emerging tool for the intraoperative quality control and evaluation of microperfusion in kidney transplantation. A dose of 0.02 mg ICG per kg body weight is recommended to ensure the quantitative assessment with SPY-Q.

Diabetes can disrupt endoplasmic reticulum (ER) homeostasis which leads to ER stress. ER stress-induced renal apoptosis seems to be involved in the development of diabetic nephropathy. The present study was designed to investigate the contribution of reduced ER stress to the beneficial effects of an angiotensin receptor blocker. Insulin-dependent diabetes mellitus was induced by streptozotocin injections to hypertensive mRen2-transgenic rats. After 2weeks animals were treated with 0.7mg/kg/day irbesartan. Blood glucose, blood pressure and protein excretion were assessed. Expression of ER stress markers was measured by real-time PCR. Immunohistochemistry was performed to detect markers of ER stress, renal damage and infiltrating cells. Glomerulosclerosis and apoptosis were evaluated. Diabetic mRen2-transgenic rats developed renal injury with proteinuria, tubulointerstitial cell proliferation as well as glomerulosclerosis and podocyte injury. Moreover, an increase in inflammation, podocyte ER stress and apoptosis was detected. Irbesartan somewhat lowered blood pressure and reduced proteinuria, tubulointerstitial cell proliferation and glomerulosclerosis. Podocyte damage was ameliorated but markers of ER stress (calnexin, grp78) and apoptosis were not reduced by irbesartan. On the other hand, inflammatory cell infiltration in the tubulointerstitium and the glomerulus was significantly attenuated. We conclude that irbesartan reduced renal damage even in a very low dose. The beneficial effects of low dose irbesartan were paralleled by a reduction of blood pressure and inflammation but not by a reduction of ER stress and apoptosis. Thus, sustained endoplasmic reticulum stress in the kidney does not necessarily lead to increased inflammation and tubulointerstitial or glomerular injury.

Intrauterine growth restriction (IUGR) is an important risk factor for cardiovascular disease. Previous studies revealed altered myocardial matrix composition after IUGR. We hypothesized that IUGR is accompanied by compromised myocardial performance independently from arterial hypertension.IUGR was induced in Wistar rats by maternal protein restriction, and hearts of male offspring were studied using echocardiography, immunohistochemistry, real-time PCR, and western blot analysis.At day 70 of life, in the absence of arterial hypertension (mean arterial blood pressure: 101.3 ± 7.1 mmHg in IUGR vs. 105.3 ± 4.6 mmHg in controls, not significant (NS)), echocardiography showed a reduced contractility (ejection fraction: 65.4 ± 1.8% in IUGR vs. 82.2 ± 1.5% in controls, P0.001) of a more distensible myocardium in IUGR rats. Altered expression patterns of myosin chains and titin isoforms and increased expression levels of atrial natriuretic peptide, Na/K-ATPase, and β-adrenergic receptor 1 were detected. A higher number of cardiac fibroblasts and vascular cross-sections were observed in IUGR rats, accompanied by elevated expression of hypoxia inducible factor 1 target genes, such as vascular endothelial growth factor and its receptors.We observed a blood pressure-independent impairment of myocardial function after IUGR, which possibly favors cardiovascular disease later in life. Some IUGR-induced myocardial changes (e.g., sarcomeric components) may partly explain the compromised cardiac performance, whereas others (e.g., elevated vascular supply) reflect compensatory mechanisms.

PURPOSE OF REVIEW To summarize the available evidence on whether a lower blood pressure (BP) treatment target can ameliorate the progression of nondiabetic chronic kidney disease (CKD), and prevent cardiovascular events in CKD patients. RECENT FINDINGS The three prospective, randomized controlled trials which addressed the question of progression of CKD suggest that a lower BP treatment goal (

Development of diabetic nephropathy is accompanied by changes in integrin-mediated cell-matrix interactions. The α8-integrin chain is specifically expressed in mesangial cells of the glomerulus. During experimental hypertension, α8-integrin plays a protective role in the glomerulus. We hypothesized that α8-integrin is involved in maintaining the integrity of the glomerulus in diabetic nephropathy. Experimental streptozotocin (STZ) diabetes led to an increased expression and glomerular deposition of α8-integrin. To test the functional role of α8-integrin, STZ diabetes was induced in mice with a homozygous (α8−/−) or heterozygous (α8+/−) deletion of the α8-integrin gene and in wild-type litters (α8+/+). Blood glucose and mean arterial blood pressure were not different in α8−/− and α8+/+ mice after 6 wk of diabetes. However, diabetic α8−/− mice developed significantly higher albuminuria and more glomerulosclerosis than diabetic α8+/+ mice. Moreover, in diabetic α8−/− mice, the number of glomerular cells staining positive for the podocyte markers WT-1 and vimentin were reduced more prominently than in diabetic α8+/+. The filtration barrier protein nephrin was downregulated in diabetic glomeruli with the strongest reduction observed in α8−/− mice. Taken together, α8−/− mice developed more severe glomerular lesions and podocyte damage after onset of STZ diabetes than α8+/+ mice, indicating that α8-integrin is protective for the structure and function of the glomerulus and maintains podocyte integrity during the development of diabetic nephropathy.

We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic < 140 and diastolic < 90 mmHg. In 5183 patients in whom measurements were available, mean blood pressure was 139.5 ± 20.4 / 79.3 ± 11.8 mmHg; 4985 (96.2%) of the patients were hypertensive. Awareness and treatment rates were > 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use.

Basal nitric oxide (NO) activity has a pivotal role in the regulation of glomerular hemodynamics, and in animal experiments, its alteration has been associated with morphological changes characteristic of diabetic nephropathy.Prospective observational-study during a mean follow-up of 2.1 years.66 hypertensive patients (aged 30 to 80 years) with type 2 diabetes and estimated glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m(2) with normoalbuminuria or microalbuminuria.Mean arterial pressure during follow-up during treatment with telmisartan or ramipril for 9 weeks, followed by treatment according to the discretion of the individual primary care physician.Renal vascular resistance, renal plasma flow, GFR, and change in renal plasma flow in response to infusion of the NO synthase inhibitor N-monomethyl-L-arginine as an indicator of basal NO activity in the renal vasculature.50 of 66 patients could be reexamined. At follow-up, mean arterial pressure decreased from 106 +/- 9.1 to 100 +/- 11 mm Hg (P0.001). Body mass index and hemoglobin A(1c) levels were unaltered. Renal vascular resistance decreased (from 128 +/- 44 to 103 +/- 30 mm Hg/mL/min/1.73 m(2); P0.001), renal plasma flow increased (from 490 +/- 133 to 589 +/- 154 mL/min/1.73 m(2); P0.001), and GFR did not change (113 +/- 22 versus 116 +/- 26 mL/min/1.73 m(2); P = 0.4) during follow-up. The decrease in renal plasma flow in response to N-monomethyl-l-arginine infusion was more pronounced at follow-up (-56.7 +/- 39 versus -73.4 +/- 48 mL/min/1.73 m(2); P = 0.02), indicating improved basal NO activity. After adjustment for possible confounders, patients with a marked decrease in mean arterial pressure showed more improved basal NO activity during follow-up than those with a less pronounced decrease in mean arterial pressure (P = 0.04).Patients were treated according to the discretion of the individual primary care physician.During follow-up, renal vascular resistance, renal plasma flow, and renal endothelial function (indicated by basal NO activity) improved. Better blood pressure control was associated with improved endothelial function of the renal vasculature, thereby potentially mediating the changes in renal hemodynamics.

We examined the effects of fluvastatin treatment on the development of kidney injury in experimental deoxycorticosterone-acetate (DOCA)-salt hypertension.Male Sprague-Dawley rats underwent unilateral nephrectomy and received subcutaneous DOCA pellets as well as 1% NaCl for drinking. Simultaneously, rats were treated with 5 mg/kg per day fluvastatin, or solvent only for 6 weeks. Mean arterial pressure was measured intraarterially. Glomerulosclerosis, interstitial fibrosis, cell proliferation, inflammation and podocyte damage were evaluated on kidney sections. Inflammatory markers were measured by real-time PCR.Mean arterial pressure was elevated in DOCA-salt-treated rats but unaltered by fluvastatin. Serum cholesterol was markedly elevated in DOCA-salt-treated rats and tended to be lower in fluvastatin-treated animals. Fluvastatin treatment decreased the mortality of DOCA-salt-treated rats. Urinary protein excretion, glomerular proliferation and macrophage infiltration as well as glomerulosclerosis were reduced by fluvastatin. Fluvastatin alleviated podocyte damage and glomerular osteopontin protein expression, which was localized in podocytes. On the contrary, interstitial fibrosis, inflammation and interstitial cell proliferation of DOCA-salt-treated rat kidneys were not influenced by fluvastatin.Statin treatment reduces mortality and glomerular damage independent from blood pressure in a low-renin model of hypertensive nephrosclerosis. A reduction of podocyte damage and macrophage infiltration may explain the beneficial effects of fluvastatin.

BACKGROUND In the heart, the alpha8 integrin chain is expressed in fibroblasts and vascular smooth-muscle cells but its functional role in the myocardium is unknown. Integrins can contribute to tissue fibrosis in several organs. We tested the hypothesis that alpha8 integrin-mediated cell-matrix interactions add to cardiac fibrotic alterations during hypertension. METHODS Desoxycorticosterone-acetate (DOCA)-salt hypertension was induced in mice homozygous for a deletion of the alpha8 integrin chain and wild-type mice. Histological and immunohistochemical evaluations were performed in heart tissue. RESULTS Blood pressure was slightly higher in DOCA-treated alpha8 integrin-deficient mice compared to DOCA-treated wild types. Expression of alpha8 integrin and its ligands fibronectin and osteopontin was increased in the hearts of DOCA-treated wild types compared to salt-loaded controls. However, relative left ventricular weights did not differ between DOCA-treated wild types and alpha8 integrin-deficient mice. Moreover, expansion of collagen I immunoreactivity and cell proliferation was similar in both groups. The number of osteopontin-positive cells was not different in DOCA-treated alpha8 integrin-deficient and DOCA-treated wild-type mice. Despite of a comparable degree of fibrosis in both groups, alpha-smooth-muscle actin and discoidin domain receptor 2 (DDR2)-positive myofibroblasts were only detected in wild-type DOCA-treated mice, not in DOCA-treated alpha8 integrin-deficient mice. CONCLUSIONS The results show that lack of alpha8 integrin does not reduce fibrotic changes in the hearts of DOCA-salt hypertensive mice. Our findings do not argue for a profibrotic effect of an increased alpha8 integrin expression in the myocardium in hypertension.

Objective We examined the contribution of high blood pressure versus direct mineralocorticoid effects to the progression of kidney inflammation and fibrosis in established experimental deoxycorticosterone-acetate (DOCA)-salt hypertension. Methods Male Sprague-Dawley rats underwent unilateral nephrectomy and received subcutaneous DOCA pellets as well as 1% NaCl for drinking. After 4 weeks of DOCA-salt hypertension, rats were either killed (n = 6), or treated with a non-hypotensive dose of spironolactone (n = 7) or triple therapy (hydrochlorothiazide, reserpine and hydralazine, n = 8) to normalize blood pressure or with vehicle (n = 19) for two further weeks. Mean arterial pressure (MAP) was measured intra-arterially. Glomerulosclerosis, interstitial fibrosis, macrophage infiltration and complement deposition were evaluated on kidney sections. Expression of collagens, chemokines and cytokines was measured by real-time PCR. Results MAP was elevated in DOCA rats, not affected by spironolactone and normalized by triple therapy. Glomerulosclerosis and interstitial fibrosis of DOCA rats were alleviated by spironolactone and triple therapy. Macrophage infiltration, complement C3 deposition and nitrotyrosine staining in the kidney were significantly reduced by spironolactone as well as triple therapy. The expression of collagens, chemokines, adhesion molecules and profibrotic cytokines in the kidney was elevated in hypertension and decreased by triple therapy but not significantly affected by spironolactone. Conclusion Direct mineralocorticoid effects as well as high blood pressure per se contribute to inflammation and fibrosis of the kidney. Oxidative stress may mediate the direct mineralocorticoid effects on kidney inflammation.

Increasing evidence indicates that inflammation of visceral organs is significantly affected by the autonomic nervous system. Such neuroimmune interactions have not been studied in the kidney. Here, we show that the rat kidney is innervated by both tyrosine hydroxylase-positive sympathetic efferent nerve fibers and calcitonin gene-related peptide-positive primary afferent nerve fibers, both of which are found in proximity to macrophages and dendritic cells. Complete surgical bilateral renal denervation was performed 2 d before glomerulonephritis was induced by injecting the monoclonal anti-Thy-1.1 antibody OX-7. Denervation significantly reduced albuminuria, mesangiolysis, formation of microaneurysms, deposition of glomerular collagen IV, and expression of TGF-beta compared with sham-operated controls. Accordingly, inflammation, identified by accumulation of interstitial macrophages and renal expression of TNF-alpha, and mesangial cell proliferation were significantly reduced. These findings indicate that autonomic renal denervation ameliorates and, by inference, innervation exacerbates acute inflammation in the kidney; therefore, neurotransmitters or neuropeptides and their receptors might represent novel targets for the treatment of acute glomerulonephritis.

Patienten mit einer chronischen Nierenerkrankung haben abhangig von der Einschrankung der glomerularen Filtrationsrate (GFR) als Mas der Niereninsuffizienz und dem Alter ein 1,5- bis 1000-fach erhohtes kardiovaskulares Risiko. Die Niereninsuffizienz an sich ist dabei ein unabhangiger Risikofaktor fur kardiovaskulare Ereignisse, auch bei Patienten mit zusatzlich vorliegender Hypertonie oder Diabetes mellitus. Bei Patienten mit bereits manifester Herzinsuffizienz oder koronarer Herzerkrankung ist die GFR der wichtigste pradiktive Faktor fur das weitere Uberleben. Proteinurie bzw. Albuminurie als Ausdruck einer Nierenerkrankung sind ebenfalls wichtige Marker und korrelieren mit dem kardiovaskularen Risiko sowohl im Bereich der Mikro- als auch Makroalbuminurie. Als pathophysiologische Mechanismen eines erhohten kardiovaskularen Risikos bei Nierenerkrankungen werden eine endotheliale Dysfunktion, oxidativer Stress, Dyslipidamie und eine verstarkte Gefasverkalkung diskutiert.

Chronic kidney disease (CKD) is associated with increased risk and worse prognosis of cardiovascular disease, including peripheral artery disease. An impaired angiogenic response to ischemia may contribute to poor outcomes of peripheral artery disease in patients with CKD. Hypoxia inducible factors (HIF) are master regulators of angiogenesis and therefore represent a promising target for therapeutic intervention. To test this we induced hind-limb ischemia in rats with CKD caused by 5/6 nephrectomy and administered two different treatments known to stabilize HIF protein in vivo : carbon monoxide and a pharmacological inhibitor of prolyl hydroxylation 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA). Expression levels of pro-angiogenic HIF target genes ( Vegf, Vegf-r1, Vegf-r2, Ho-1 ) were measured by qRT-PCR. Capillary density was measured by CD31 immunofluorescence staining and HIF expression was evaluated by immunohistochemistry. Capillary density in ischemic skeletal muscle was significantly lower in CKD animals compared to sham controls. Rats with CKD showed significantly lower expression of HIF and all measured pro-angiogenic HIF target genes, including VEGF. Both HIF stabilizing treatments rescued HIF target gene expression in animals with CKD and led to significantly higher ischemia-induced capillary sprouting compared to untreated controls. ICA was effective regardless of whether it was administered before or after induction of ischemia and led to a HIF expression in skeletal muscle. Thus, impaired ischemia-induced angiogenesis in rats with CKD can be improved by HIF stabilization, even if started after onset of ischemia.

In contrast to other sympathetic outflow tracts, renal sympathetic nerve activity (RSNA) decreases in response to hypotensive hemorrhage. The functional significance of this “paradox” is not known. We tested the hypothesis that RSNA modulates renal perfusion and thus erythropoietin (EPO) release after transient hypotensive hemorrhage in anesthetized rats. Plasma EPO was measured before and after 30 min of transient hypotensive hemorrhage (i.e., −40 mmHg from mean baseline blood pressure, followed by reinfusion of shed blood) and 120 min thereafter in sham-denervated rats, and after renal denervation (DNX) or bilateral cervical vagotomy (VX) to abolish/blunt the RSNA decrease mediated by a cardiopulmonary reflex. RSNA, renal Doppler flow, renal vascular resistance (RVR), resistance index, and oxygen delivery/uptake (Do2/V̇o2) were measured. RSNA decreased in intact animals (−40 ± 5% from baseline, P < 0.05). This was blunted by VX. With intact nerves, EPO level did not increase. In DNX rats, EPO was increased at minute 120 (49 ± 3 vs. 74 ± 2 mU/ml; P < 0.05), in VX rats this (47 ± 2 vs. 62 ± 4 mU/ml; P < 0.05) was less pronounced. Do2 in DNX rats was lower compared with intact and VX rats (0.25 ± 0.04 vs. 0.51 ± 0.06 and 0.54 ± 0.05 ml O2/min; P < 0.05) due to lower Doppler flow and increased RVR. RVR and Do2 were similar in intact and VX rats, but resistance index differed between all groups (0.70 ± 0.02 vs. 0.78 ± 0.02 vs. 0.85 ± 0.02; P < 0.05, intact vs. VX vs. DNX), indicating differential reactivity of renal vasculature. V̇o2 was unaffected by VX and DNX. Renal sympathoinhibition during hypotensive hemorrhage might help to preserve sufficient oxygenation of renal tissue by modulation of hemodynamic mechanisms that act to adapt renal oxygen availability to demand.

Objectives In patients with hypertension left ventricular hypertrophy (LVH) is associated with genetic variations of the angiotensin type 2 receptor (AT2R). Hypertension and LVH are often aggravated by salt intake. Our objective was to assess the relationship between AT2R gene variation and salt intake and their impact on left ventricular mass (LVM). Methods and results In 205 subjects with normal or mildly elevated blood pressure, we assessed sodium intake and left ventricular structure and function by echocardiography. Intronic +1,675 G/A polymorphism of the AT2R gene was investigated. A-allele carriers had a greater LVM (P = 0.049) than G-allele carriers. Independent of diet, septal wall thickness was higher in A-allele carriers (P = 0.001). Fractional fibre shortening was greater in A-allele carriers (P = 0.034), and the velocity of circumferential fibre shortening tended to be greater in A-allele carriers (P = 0.057). When the two groups were stratified according to their salt intake, only G-allele carriers displayed a modulating effect of salt intake on LVM. Covariance analysis revealed that there was a trend towards a modulating effect of salt intake on LVM, even after taking blood pressure into account (P = 0.054). Conclusion Our data clearly support the notion that LVM is influenced by AT2R polymorphisms. Furthermore, G-allele carriers in particular appear to be susceptible to a modifying effect of increased salt intake on LVM.

The renin-angiotensin system is a major regulatory system of cardiovascular and renal function. Basic research has revealed exciting new aspects, which could lead to novel or modified therapeutic approaches. Renin-angiotensin system blockade exerts potent antiatherosclerotic effects, which are mediated by their antihypertensive, anti-inflammatory, antiproliferative, and oxidative stress lowering properties. Inhibitors of the system-ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are now first-line treatments for hypertensive target organ damage and progressive renal disease. Their effects are greater than expected by their ability to lower blood pressure alone. Angiotensin receptor blockers reduce the frequency of atrial fibrillation and stroke. Renin-angiotensin system blockade delays or avoids the onset of type 2 diabetes and prevents cardiovascular and renal events in diabetic patients. Thus, blockade of this system will remain a cornerstone of our strategies to reduce cardiovascular risk.

Induction of streptozotocin (STZ) diabetes in hypertensive rats transgenic for the mouse ren-2 gene (TGR) has been described as a model of progressive diabetic nephropathy. We investigated the long-term course of STZ diabetes in TGR and appropriate Sprague-Dawley control rats (SD) and tested the role of angiotensin-dependent hypertension by treating rats with the angiotensin II type 1 receptor blocker losartan (1 mg·kg−1·day−1) via osmotic minipumps. Five weeks after STZ injection, diabetes developed in TGR and SD. Urinary albumin excretion was increased by diabetes and, to a much higher degree, by hypertension. The effects of hypertension and diabetes were not additive, and only the effects of hypertension were ameliorated by losartan. A similar pattern was observed for cell proliferation and macrophage infiltration in the kidney. In contrast, the effects of hypertension and diabetes on glomerular collagen IV accumulation were additive 5 wk after STZ injection. In a long-term study for 20 wk after STZ, survival was better in STZ-treated TGR than in normoglycemic TGR, whereas all SD survived. Impaired creatinine clearance and increased macrophage infiltration as well as glomerular and interstitial matrix deposition were prominent in TGR compared with SD, regardless of the presence or absence of diabetes. In conclusion, STZ diabetes in TGR may be useful to study glomerular and interstitial matrix deposition early in the course of diabetes. However, the long-term course of this animal model resembles severe hypertensive nephrosclerosis, rather than progressive diabetic nephropathy.

Background: Cardiomyopathy in experimental renal insufficiency is putatively influenced by neurogenic pathways of renal origin. We wondered if cardiac neurogenic effects in congestive heart failure could likewise harm the kidney. We hypothesized that increased renal sympathetic nerve activity (RSNA) in rats with congestive heart failure after myocardial infarction (CHF) induces renal structural damage. Methods: 21 day after induction of CHF renal morphology was evaluated by immunohistology (interstitial and glomerular mononuclear cell infiltration (ED1), cell proliferation (PCNA), collagen I,III,IV,V,VI, laminin und fibronectin). RSNA was assessed by volume challenge (VE) to decrease RSNA. CHF and control rats were investigated with and without renal denervation (DNX). Blood pressure (BP), heart rate (HR) and RSNA were recorded. Nodose ganglion neurons (NGN) with vagal cardiac afferents were cultured for 1 day. Whole cell recordings were obtained and current-voltage relationships established. Cells were characterized by osmomechanical stress with a mannitol solution. Results: In CHF rats with intact renal nerves (nonDNX) formation of collagen I occurred, that was reduced after DNX (12.2+0.7 %area vs. 9.1+1.1 %area*, n=6, * p Conclusion: CHF induced subtle renal structural damage due to increased renal sympathetic tone which was likely due to altered NGN mechanosensitivity. Afferent nerve units from cardiovascular organs obviously form a complex sympathomodulatory network.

Intrauterine growth retardation (IUGR) aggravates the course of acute mesangioproliferative glomerulonephritis (GN) in the rat. Observational studies in children suggest that IUGR may be associated with a severe course of kidney diseases such as IgA nephropathy. We tested the hypothesis that IUGR leads to aggravation of acute mesangioproliferative GN in former IUGR rats. IUGR was induced in Wistar rats by isocaloric protein restriction in pregnant dams. Litter size was reduced to six male neonates in low protein animals (LP) and normal protein animals (NP). At 8 weeks GN was induced by injection of an anti-Thy-1.1 antibody. Rats were killed on days 4 and 14 after induction of GN and kidneys were investigated for inflammation and sclerosis using real-time polymerase chain reaction and histological methods. On day 4 after induction of GN, LP animals showed more glomerulosclerosis and tubulointerstitial lesions. On day 14, inflammatory markers (expression of monocyte chemoattractant protein 1, osteopontin, tumor necrosis factor and interleukin-6), extracellular matrix accumulation and markers of sclerosis (plasminogen activator inhibitor-1 expression, transforming growth factor-beta1 expression, score for glomerulosclerosis, glomerular deposition of collagen I and collagen IV) were more severe in LP animals. Some degree of induction of inflammatory and profibrotic markers was also present in non-nephritic LP animals. However, these rats did not display marked glomerulosclerosis or interstitial fibrosis. We conclude that after IUGR inflammatory damage is aggravated and the reparation of the kidney is impaired during the course of acute mesangioproliferative GN, leading to more sclerotic lesions.

The microfibrillar protein fibrillin-1 is a component of the mesangial matrix. Defects in fibrillin-1 predisposes individuals to vascular damage in Marfan syndrome, but the role of fibrillin-1 in kidney disease is unknown. We hypothesized that fibrillin-1 is involved in hypertensive or diabetic glomerular disease. DOCA-salt hypertension or streptozotocin (STZ) diabetes led to a significant increase in glomerular fibrillin-1 deposition. To test the functional role of fibrillin-1, DOCA hypertension and STZ diabetes were induced in mice homozygous for a mutation leading to a fivefold lower expression of fibrillin-1 (mgR/mgR). Untreated male mgR/mgR mice usually die from aortic dissection during the first 4 mo of life. All DOCA-treated mgR/mgR mice died within 2 wk after onset of DOCA treatment. DOCA-treated heterozygous (mgR/+) and their wild-type littermates displayed similar blood pressure levels, but albuminuria was significantly lower in mgR/+ than in wild-type mice after DOCA treatment. Similarly, STZ diabetic mgR/mgR and mgR/+ developed lower albuminuria than wild-type mice despite higher blood glucose levels in mgR/mgR and mgR/+ compared with wild-type mice. Blood pressure, blood glucose, and albuminuria did not differ among untreated mgR/mgR, mgR/+, and wild-type mice, respectively. In diabetic mgR/+ and mgR/mgR, but not in wild-type mice, an induction of glomerular decorin expression was observed. Thus underexpression of fibrillin-1 predisposes individuals to lethal aortic dissection in the presence of hypertension. On the other hand, albuminuria as a parameter of microvascular damage in hypertension and diabetes was ameliorated in fibrillin-1-underexpressing mice, possibly due to a compensatory upregulation of decorin. We conclude that fibrillin-1 may contribute to glomerular damage in hypertensive and diabetic kidney disease.

Kidney disease is associated with increased cardiovascular morbidity, but underlying mechanisms are poorly understood. We tested the hypothesis that chronic renal insufficiency impairs angioadaptation in a rat model of hindlimb ischemia. Twenty male Sprague-Dawley rats (8 weeks old) underwent subtotal nephrectomy (5/6SNX) or sham surgery (each n=10). Ten weeks later, unilateral hindlimb ischemia was induced in all animals. Hindlimb perfusion was assessed by laser Doppler perfusion imaging and fluorescent microsphere injection studies 2 weeks after surgery. Ischemia-induced angiogenesis was measured by analyzing capillary density using CD31 immunofluorescence. Expression of vascular endothelial growth factor (VEGF), its receptors (VEGFRs) and inducible as well as endothelial nitric oxide (NO) synthase was measured by real-time reverse transcription-polymerase chain reaction. Laser Doppler hindpaw perfusion was significantly reduced in 5/6SNX compared to sham-operated animals. Impaired hindlimb re-perfusion in 5/6SNX vs control rats was confirmed by fluorescent microsphere injection studies (relative perfusion of ischemic vs non-ischemic limb: 68.9+/-6.4 vs 92.4+/-3.6%, P=0.005). Ischemic skeletal muscle neovascularization increased to a greater extent in sham-operated compared to 5/6SNX rats (69+/-8 vs 29+/-7%, P0.05). VEGF and VEGFR-1/2 mRNA expression increased in ischemic hindlimbs of control rats, whereas no change or a decrease was observed in 5/6SNX. In contrast, inducible and endothelial NO synthase expression did not significantly differ between sham and 5/6SNX rats. Chronic renal insufficiency impairs angiogenesis and limb perfusion in a rat hindlimb ischemia model. Impaired angioadaptation may contribute to the poor prognosis of patients with renal failure suffering from peripheral arterial disease.

Background. Ren-2 transgenic hypertensive rats develop malignant hypertensive nephrosclerosis despite low to normal plasma angiotensin II and suppressed renal renin. We tested the hypothesis that local angiotensin II formation occurs at sites of renal vascular and interstitial injury in this model. Methods. Heterozygous Ren-2 transgenic rats were compared with normotensive Sprague-Dawley-Hannover control rats and Ren-2 transgenic rats treated with a very low dose of an angiotensin II type 1 (AT 1 ) receptor antagonist, 1 mg/kg/day losartan, for 4 weeks. Blood pressure measurements, quantifications of urinary albumin, plasma and tissue angiotensin II as well as immunohistochemical analyses were performed. Results. Systolic blood pressure was not affected by losartan during the study but intra-arterial recordings revealed a decrease of blood pressure. Losartan reduced albumin excretion, cell proliferation, macrophage influx, collagen I and collagen IV deposition. Plasma angiotensin II was decreased, while kidney tissue angiotensin II content was increased in Ren-2 transgenic rats compared with control rats. In Ren-2 transgenic rats, juxtaglomerular renin and angiotensin II staining were reduced, but there was a marked angiotensin II staining at foci of tubulo-interstitial fibrosis and at proliferative malignant vascular lesions. Conclusion. We conclude that local angiotensin II formation is increased in proliferative or fibrotic kidney lesions in the Ren-2 transgenic rat. Local angiotensin II formation may help to explain why the AT 1 receptor antagonist prevents or ameliorates this transgenic model of malignant nephrosclerosis despite low to normal plasma angiotensin II and suppressed renal renin.

Sensory nerve fibers from the dorsal root ganglia (DRG) may contribute to the regulation of peripheral vascular resistance. Axons of DRG neurons of the lower thoracic cord project mainly to resistance vessels in the lower limbs, likely opposing the vasoconstrictor effects of the sympathetic activity. This mechanism might be of importance in hypertension with increased sympathetic activity. We tested the hypothesis that sensory neurons of the DRG in the lower thoracic cord show an altered sensitivity to mechanical stimuli in hypertension. Neurons from DRG (T11 to L1) of rats with hypertension (2 kidney-1 clip hypertensive rats and 5 of 6 nephrectomized rats) were cultured on coverslips. Current time relationships were established with whole-cell patch recordings. Cells were characterized under control conditions and after exposure to hypoosmotic solutions to induce mechanical stress. Neurons with projections to the kidney were studied for comparison. The hypoosmotic extracellular medium induced a significant change in conductance of the cells in all of the groups of rats. In hypertensive rats, responses of cells with hindlimb axons were significantly different from controls: (2 kidney-1 clip hypertensives: δ−351±52 pA and 5 of 6 nephrectomized rats: δ−372±43 pA versus controls: δ−190±25 pA; P

Adrenomedullin reduces mesangial cell number and glomerular inflammation in experimental mesangioproliferative glomerulonephritis. Background Adrenomedullin (ADM) is a vasodilator peptide that is abundantly expressed in the kidney. ADM has antiproliferative effects on glomerular mesangial cells (MC) in vitro. Whether or not treatment with ADM can reduce MC proliferation in vivo [i.e., in mesangioproliferative glomerulonephritis (GN)] is unknown. We tested the hypothesis that ADM substitution reduces MC proliferation in GN. Methods GN in rats was induced by injection of an anti-Thy-1.1 antibody. Rats received osmotic minipumps, which continuously delivered rat ADM (500 ng/hour, N = 11), or vehicle ( N = 13) from day 3 to day 6 after GN induction. Rats were sacrificed 6 days after induction of GN. On kidney sections, cells staining positive for proliferating cell nuclear antigen, mesangial cells, monocytes, and apoptotic cells were counted. Parameters of inflammation and fibrosis were measured in renal cortex and sieved glomeruli by real-time polymerase chain reaction (PCR). Results Systolic blood pressure, diuresis, albuminuria, creatinine clearance, microaneurysm formation, and mesangial matrix expansion were not influenced by ADM infusion. However, ADM treatment significantly reduced the number of MC, showed a tendency to reduce total glomerular cell proliferation, and significantly increased apoptosis. ADM-treated GN animals showed significantly less glomerular monocyte infiltration. ADM treatment normalized transforming growth factor (TGF)-β1 mRNA expression and reduced monocyte chemoattractant protein-1 (MCP-1), osteopontin, plasminogen activator inhibitor-1 (PAI-1), collagen I, and collagen III mRNA expression significantly. Conclusion Exogenous ADM infusion reduces MC number and glomerular monocyte infiltration in the state of mesangial proliferation during acute experimental mesangioproliferative GN. These findings indicate that ADM can influence the course of mesangioproliferative GN.

This review focuses on the association between mild renal insufficiency (stage 2 and 3 of chronic kidney disease) and cardiovascular disease and discusses therapeutic options. Although the association of chronic renal insufficiency and cardiovascular risk was first shown in patients with end-stage renal disease, even minor renal dysfunction is now established as an independent risk for atherosclerotic cardiovascular disease. The association has been established in patients with a high cardiovascular risk but also in the general population. Treatment with angiotensin-converting enzyme inhibitors and statins can reduce cardiovascular morbidity and mortality in patients with renal insufficiency. Coronary revascularization improves the prognosis in patients with minor renal dysfunction, but there is still an underutilization of coronary revascularization procedures in people with renal insufficiency. The use of coronary stenting has now reduced the incidence of restenosis in these patients, and there is hope that the development of new devices will improve the prognosis in patients with renal insufficiency as well. Nevertheless, people with cardiovascular disease and renal insufficiency die significantly more often than people without renal insufficiency independent of prior successful treatment. Further investigations should focus on the causes of and possible preventive interventions for the staggering cardiovascular risk in the ever-increasing number of people with minor renal dysfunction.

Background. The genetic background may exert important modifying effects on the course and severity of experimental kidney diseases in mice. We investi- gated its influence on the development of hypertension and renal injury following treatment with deoxycorti- costerone acetate (DOCA) salt in several mouse strains. Methods. Four mouse strains were used for compar- ison: 129/Sv, C57BL/6 and F1 and F2 intercrosses of 129/SvC57BL/6. Male mice were uninephrectomized and DOCA hypertension was induced for 6 weeks. DOCA animals and controls received 1% NaCl for drinking. Renal damage was evaluated following mea- surements of blood pressure, urine albumin and renal matrix expansion. Results. DOCA-induced blood pressure increase, glo- merulosclerosis, interstitial fibrosis and albuminuria were markedly higher in 129/Sv than in C57BL/6 mice. F1 and F2 intercrosses displayed intermediate blood pressure, glomerular and interstitial fibrosis compa- rable to C57BL/6 but albuminuria as high as 129/Sv mice. Conclusions. 129/Sv mice are more susceptible to the development of DOCA-induced high blood pressure and renal damage than C57BL/6 mice. Intercrosses of both strains show a complex and non-uniform segregation of the susceptibility to DOCA-salt hyper- tension and nephrosclerosis.

In the kidney, the alpha8 integrin chain is expressed in glomerular mesangial cells. The alpha8 integrin plays a role in early nephrogenesis but its functional role in the adult kidney is unknown. We tested the hypothesis that alpha8 integrin-mediated cell-matrix interactions are important to maintain the integrity of the glomerulus in arterial hypertension. Desoxycorticosterone (DOCA)-salt hypertension was induced in mice homozygous for a deletion of the alpha8 integrin chain and wild-type mice. Blood pressure, albumin excretion, total renal mass, and glomerular filtration in DOCA-treated alpha8-deficient mice were comparable to DOCA-treated wild types. DOCA-treated wild types showed increased glomerular immunostaining for alpha8 integrin compared to salt-loaded and untreated controls, whereas the glomeruli of alpha8-deficient mice always stained negative. Morphometric studies revealed similar degrees of glomerulosclerosis in DOCA-treated alpha8-deficient and DOCA-treated wild-type mice. However, DOCA-treated alpha8-deficient mice had a higher score of capillary widening (mesangiolysis) than DOCA-treated wild-type mice, which was confirmed in two additional wild-type strains. Moreover, in DOCA-treated alpha8-deficient mice, glomerular fibrin deposits were more frequent than in DOCA-treated wild types. The results show that lack of alpha8 is associated with increased susceptibility to glomerular capillary destruction in DOCA salt hypertension, whereas it does not seem to play a major role in the development of fibrosis or glomerulosclerosis. Our findings indicate that mesangial alpha8 integrin contributes to maintain the integrity of the glomerular capillary tuft during mechanical stress, eg, in hypertension.

Background A main challenge for targeting chronic kidney disease (CKD) is the heterogeneity of its causes, co-morbidities and outcomes. Patients under nephrological care represent an important reference population, but knowledge about their characteristics is limited. Methods We enrolled 5217 carefully phenotyped patients with moderate CKD [estimated glomerular filtration rate (eGFR) 30–60 mL/min per 1.73 m2 or overt proteinuria at higher eGFR] under routine care of nephrologists into the German Chronic Kidney Disease (GCKD) study, thereby establishing the currently worldwide largest CKD cohort. Results The cohort has 60% men, a mean age (±SD) of 60 ± 12 years, a mean eGFR of 47 ± 17 mL/min per 1.73 m2 and a median (IQR) urinary albumin/creatinine ratio of 51 (9–392) mg/g. Assessment of causes of CKD revealed a high degree of uncertainty, with the leading cause unknown in 20% and frequent suspicion of multifactorial pathogenesis. Thirty-five per cent of patients had diabetes, but only 15% were considered to have diabetic nephropathy. Cardiovascular disease prevalence was high (32%, excluding hypertension); prevalent risk factors included smoking (59% current or former smokers) and obesity (43% with BMI >30). Despite widespread use of anti-hypertensive medication, only 52% of the cohort had an office blood pressure

Background With increased waiting times for kidney transplantation, marginal organs from expanded criteria donors (ECD) are increasingly offered for allocation. In addition to ECD status, donors may have suffered from acute kidney injury (AKI) prior to organ procurement. Methods In this retrospective cohort study, we studied short-term allograft function in 517 kidney transplants performed between the years 2008–2014. Recipients of allografts from deceased organ donors were categorized as standard criteria donors (SCD) or ECD with or without AKI defined by RIFLE criteria. Results Of 382 deceased donations, 174 (45.5%) were classified as ECD and 63 (16.5%) fulfilled AKI criteria. Donor creatinine on hospital admission was similar, whereas creatinine before organ procurement differed (p

Background — Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect. Methods and Results — Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (n=14) or 3 (n=12) mg · kg −1 · d −1 or solvent (n=27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects. Conclusions — Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.

OBJECTIVESOur study goal was to analyze whether gene variants of angiotensin II type 2-receptor (AT2-R) modulate the effects of angiotensin II on the left ventricle (LV).BACKGROUNDExperimental data suggest that angiotensin II modifies ventricular growth responses via angiotensin II type 1-receptors (AT1-R) and AT2-R.METHODSIn 120 white, young male subjects with normal or mildly elevated blood pressure, we assessed plasma angiotensin II and aldosterone concentrations (RIA), 24-h urinary sodium excretion, 24-h ambulatory blood pressure and LV structure (two-dimensional guided M-mode echocardiography). The intronic +1675 G/A polymorphism of the X-chromosomal located AT2-R gene was investigated by single-strand conformational polymorphism analysis and DNA-sequencing.RESULTSHypertensive subjects with the A-allele had a greater LV posterior (11.0 ± 1.3 vs. 9.9 ± 1.3 mm, p < 0.001), septal (11.8 ± 1.4 vs. 10.1 ± 1.2 mm, p < 0.001) and relative wall thickness (0.44 ± 0.06 vs. 0.39 ± 0.06, p < 0.01) as well as LV mass index (138 ± 23 vs. 120 ± 13 g/m2, p < 0.001) than those with the G-allele. Confounding factors (i.e., body mass index and surface area, plasma angiotensin II, sodium excretion, systolic and diastolic ambulatory blood pressure) were similar between the two genotypes. In normotensive subjects, relative wall thickness (0.36 ± 0.05 vs. 0.35 ± 0.05) and LV mass index (115 ± 21 vs. 112 ± 17 g/m2) were nearly identical across the two genotypes, with similar confounding variables.CONCLUSIONSOur data indicate that the X-chromosomal located +1675 G/A-polymorphism of the AT2-R gene is associated with LV structure in young male humans with early structural changes of the heart due to arterial hypertension.