Preglomerular Vessels Research Articles

Effects of levosimendan on renal blood flow and glomerular filtration in patients with acute kidney injury after cardiac surgery: a double blind, randomized placebo-controlled study

BackgroundAcute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support.MethodsIn this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvO2) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70–80 mmHg. Intra-group differences were tested by Mann–Whitney U-tests, and a linear mixed model was used to test time and group interaction.ResultsTwenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, p = 0.030), and the estimated GFR was lower (46 ± 12 vs 57 ± 11 ml/min/1.73 m2, p = 0.025). Levosimendan induced a significantly (p = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance (− 18% vs. − 4%, respectively, p = 0.043). There was a trend for a minor increase in glomerular filtration rate with levosimendan (4.5%, p = 0.079), which did differ significantly from the placebo group (p = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group (p = 0.012).ConclusionsIn hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation.Trial registrationNCT02531724, prospectly registered on 08/20/2015. https://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1

Enhanced Myogenic Constriction in the SHR Preglomerular Vessels Is Mediated by Thromboxane A2 Synthesis.

BackgroundSpontaneously Hypertensive Rats (SHR) have chronically elevated blood pressures at 30 weeks of age (systolic: 191.0 ± 1.0, diastolic: 128.8 ± 0.9). However, despite this chronic malignant hypertension, SHR kidneys remain relatively free of pathology due to having an augmented myogenic constriction (MC). We hypothesized that the enhanced MC in the SHR preglomerular vessels was due to increased prostaglandin and decreased nitric oxide (NO) synthesis, providing renal protection.MethodsSHR and Wistar Kyoto (WKY) arcuate and mesenteric arteries were treated with indomethacin (prostaglandin synthesis inhibitor), N omega-nitro-L-arginine (L-NNA, NO synthase inhibitor), and nifedipine (L-type calcium channel blocker); and MC was measured in these vessels. The role of endothelium in MC was examined by removing endothelium from WKY and SHR preglomerular and mesenteric arteries using human hair, and measuring MC. We also studied the source of prostaglandin in the SHR by treating endothelium-removed arcuate arteries with indomethacin and furegrelate (thromboxane synthase inhibitor).ResultsMC was enhanced in the SHR preglomerular vessels but not the mesenteric arteries. Indomethacin and LNNA removed the enhanced MC in the SHR. Nifedipine also inhibited MC in both WKY and SHR arcuate and mesenteric arteries. Removing endothelium did not change MC in either arcuate or mesenteric arteries of WKY and SHR rats; and did not remove the augmented MC in the SHR arcuate arteries. Indomethacin and furegrelate decreased MC in endothelium-removed SHR arcuate arteries and obliterated the enhanced MC in the SHR.ConclusionThe enhanced MC in the SHR arcuate arteries was due to thromboxane A2 synthesis from the tunica media and/or adventitia layers. MC was not dependent on endothelium, but was dependent on L-type calcium channels. Nevertheless, SHR arcuate arteries displayed differential intracellular calcium signaling compared to the WKYs.

Characteristic morphological changes in anti-VEGF therapy-induced glomerular microangiopathy.

Agents targeting vascular endothelial growth factor (VEGF) have increasingly been used for the treatment of advanced malignancies, and have been found to induce renal thrombotic microangiopathy (TMA) and proteinuria. However, histomorphological changes in human biopsies in this setting and the underlying mechanism are not yet fully understood. Therefore, we collected renal biopsy cases with a history of aVEGF therapy to review and compare morphological kidney changes in this context. Renal biopsies of 15 patients who had received anti-VEGF (aVEGF) therapy evaluated between 2013 and 2017 at a single centre were morphologically characterised with light microscopy, electron microscopy, and immunohistochemistry (IgA, IgG, IgM, C1q, and C3), and compared with cases with acute TMA caused by atypical haemolytic-uraemic syndrome or hypertension. Morphological overlap with immune complex and cryoglobulinaemic membranoproliferative glomerulonephritis, diabetic glomerulopathy and pre-eclampsia-induced glomerulopathy are discussed. Segmental glomerular capillary microaneurysms and segmental hyalinosis were typical morphological features of aVEGF therapy-induced glomerular microangiopathy, whereas fibrin or platelet thrombi or fragmented erythrocytes were rarely found or were absent. aVEGF therapy-associated microangiopathy was diffusely distributed in the glomeruli, spared preglomerular vessels, and showed morphological characteristics of chronic TMA. In individual cases, aVEGF therapy-induced glomerular microangiopathy was accompanied by immune-complex glomerulonephritis. aVEGF therapy-induced glomerular microangiopathy has a characteristic morphology and clinical presentation that helps to differentiate it from other causes of TMA. Awareness of these light microscopic findings allows identification of aVEGF therapy as a trigger of renal disease in critically ill cancer patients, and might therefore help in deciding on further therapy.

HUBUNGAN KADAR ASAM URAT DENGAN TEKANAN DARAH PADA REMAJA OBESITAS DI KOTA SEMARANG

Background : Obesity in adolescents may cause elevated uric acid levels, leading to increased blood pressure. This occurs as a result of high uric acid levels inducing arteriolopathy in preglomerular vessels. Consequently, the autoregulator response of the afferent arterioles is impaired and eventually causing hypertension. This study aimed to determine the association of uric acid levels with blood pressure in obese adolescents. Adolescent with hypertension could continue in adulthood and had an higher increased risk of mortality. Objective : To analyze correlation of serum uric acid with blood pressure in obese adolescent in SemarangMethods : This was an observational, cross-sectional study with fifty-three subjects selected through consecutive sampling. Food intakes were assessed using Semi Quantitative Food Frequency Questionare. Serum uric acid levels were measured by Uricase PAP, while physical activity levels were determined by Short International Physical Activity Questionare. Data were analyzed using Rank-Spearman test. Result : Mean serum uric acid levels in male adolescents was 4.897±1.223 mg/dL with an average systolic blood pressure of 1.219±9.544 and a mean diastolic blood pressure of 85.85±8.359. In female subjects, the mean serum uric acid levels was 4.841±0.883 mg/dL with an average systolic blood pressure of 1.175±9.653 and an average diastolic blood pressure of 81.67±8.348. Serum uric acid levels were significantly correlated with systolic blood pressure (p = 0.000; r=0,495) and diastolic blood pressure (p = 0.010, r=0,325).Conclusion : Serum uric acid levels were significantly correlated with blood pressure among obese adolescents in Semarang.

Dihydropyridine calcium channel blockers and renal disease.

Although blood pressure control is considered the main mechanism for preventing the progression of chronic kidney disease (CKD), angiotensin-converting enzyme inhibitors and angiotensin receptors blockers have an additional organ-protective role. The effects of calcium channel blockers (CCBs) in renal disease are not so clearly defined. CCBs have pleiotropic effects that might contribute to protection of the kidney, such as attenuating the mesangial entrapment of macromolecules, countervailing the mitogenic effect of platelet-derived growth factors and platelet-activating factors and suppressing mesangial cell proliferation. Some evidence has accumulated in recent years demonstrating that the new dihydropyridinic CCBs (such as lercanidipine or efonidipine) may affect both postglomerular and preglomerular vessels, resulting in a decreased filtration fraction and nephroprotective effect. Increasing clinical and experimental evidence supports this view and the use of CCBs in CKD hypertensive patients.

Renovascular remodeling and renal injury after extended angiotensin II infusion.

Chronic angiotensin II (ANG II) infusion for 1 or 2 wk leads to progressive hypertension and induces inward hypertrophic remodeling in preglomerular vessels, which is associated with increased renal vascular resistance (RVR) and decreased glomerular perfusion. Considering the ability of preglomerular vessels to exhibit adaptive responses, the present study was performed to evaluate glomerular perfusion and renal function after 6 wk of ANG II infusion. To address this study, male Wistar rats were submitted to sham surgery (control) or osmotic minipump insertion (ANG II 200 ng·kg(-1)·min(-1), 42 days). A group of animals was treated or cotreated with losartan (10 mg·kg(-1)·day(-1)), an AT1 receptor antagonist, between days 28 and 42 Chronic ANG II infusion increased systolic blood pressure to 185 ± 4 compared with 108 ± 2 mmHg in control rats. Concomitantly, ANG II-induced hypertension increased intrarenal ANG II level and consequently, preglomerular and glomerular injury. Under this condition, ANG II enhanced the total renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow and induced pressure natriuresis. These changes were accompanied by lower RVR and enlargement of the lumen of interlobular arteries and afferent arterioles, consistent with impairment of renal autoregulatory capability and outward preglomerular remodeling. The glomerular injury culminated with podocyte effacement, albuminuria, tubulointerstitial macrophage infiltration and intrarenal extracellular matrix accumulation. Losartan attenuated most of the effects of ANG II. Our findings provide new information regarding the contribution of ANG II infusion over 2 wk to renal hemodynamics and function via the AT1 receptor.

Cells of renin lineage express hypoxia inducible factor 2α following experimental ureteral obstruction.

BackgroundRecent studies indicate that mural cells of the preglomerular vessels, known as cells of renin lineage (CoRL), contribute to repair and regeneration of injured kidney glomeruli. However, their potential roles in tubulointerstitial disease are less understood. The aim of this study was to better understand CoRL number and distribution following UUO so that future mechanistic studies could be undertaken.MethodsWe mapped the fate of CoRL in adult Ren1cCreER x Rs-tdTomato-R reporter mice that underwent UUO. Kidney biopsies from sham and UUO-subjected mice on days 3, 7, and 14 were evaluated by immunohistochemistry.ResultsIn sham animals, CoRL were restricted to juxtaglomerular location. At day 7 following UUO, CoRL increased two-fold, were perivascular in location, and co-expressed pericyte markers (PDGFßR, NG2), but did not express renin. At day 14 post UUO, labeled CoRL detached from vessels and were present in the interstitium, in areas of fibrosis, where they now expressed the myofibroblast marker alpha-smooth muscle actin. The increase in CoRL was likely due to proliferation as marked by BrdU labeling, and migration from the cortex. Following UUO starting from day 3, active hypoxia inducible factor-2α was detected in nuclei in labeled CoRL, in the cortex, but not those cells found in medulla.ConclusionsWe have demonstrated that arteriolar CoRL are potential kidney progenitors that may contribute to the initial vascular regeneration. However, in chronic kidney injury (≥14 days post UUO), perivascular CoRL transition to myofibroblast-like cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0216-0) contains supplementary material, which is available to authorized users.

Connexin 40 is dispensable for vascular renin cell recruitment but is indispensable for vascular baroreceptor control of renin secretion.

Defects of the gap junction protein connexin 40 (Cx40) in renin-secreting cells (RSCs) of the kidney lead to a shift of the localization of RSCs from the media layer of afferent arterioles to the periglomerular interstitium. The dislocation of RSCs goes in parallel with elevated plasma renin levels, impaired pressure control of renin secretion, and hypertension. The reasons for the extravascular shift of RSCs and the blunted pressure regulation of renin secretion caused by the absence of Cx40 are still unclear. We have therefore addressed the question if Cx40 is essential for the metaplastic transformation of preglomerular vascular smooth muscle cells (SMCs) into RSCs and if Cx40 is essential for the pressure control of renin secretion from RSCs located in the media layer of afferent arterioles. For our study, we used mice lacking the angiotensin II type 1A (AT1A) receptors, which display a prominent and reversible salt-sensitive metaplastic transformation of SMCs into RSCs. This mouse line was crossed with Cx40-deficient mice to obtain AT1A and Cx40 double deleted mice. The kidneys of AT1A (-/-)Cx40(-/-) mice kept on normal salt (0.3 %) displayed RSCs both in the inner media layer of preglomerular vessels and in the periglomerular interstitium. In contrast to hypotensive AT1A (-/-) (mean bp syst 112 mmHg) and hypertensive Cx40(-/-) (mean bp syst 160 mmHg) mice AT1A (-/-)Cx40(-/-) mice were normotensive(mean bp syst 130 mmHg). Pressure regulation of renin secretion from isolated kidneys was normal in AT1A (-/-) mice, but was absent in AT1A (-/-)Cx40(-/-) mice alike in Cx40(-/-) mice. Low-salt diet (0.02 %) increased RSC numbers in the media layer, whilst high-salt diet (4 %) caused disappearance of RSCs in the media layer but not in the periglomerular interstitium. Blood pressure was clearly salt sensitive both in AT1A (-/-) and in AT1A (-/-)Cx40(-/-) mice but was shifted to higher pressure values in the latter genotype. Our data indicate that Cx40 is not a requirement for intramural vascular localization of RSCs nor for reversible metaplastic transformation of SMCs into RSCs. Therefore, the ectopic localization of RSCs in Cx40(-/-) kidneys is more likely due to a disturbed intercellular communication rather than being the result of chronic overactivation of the renin-angiotensin-aldosterone system or hypertension. Moreover, our findings suggest that Cx40 is a requirement for the pressure control of renin secretion irrespective of the localization of RSCs.

Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension.

This study tested the hypothesis that P2Y12 receptor blockade with clopidogrel preserves renal autoregulatory ability during ANG II-induced hypertension. Clopidogrel was administered orally to male Sprague-Dawley rats chronically infused with ANG II. After 14 days of treatment, whole kidney autoregulation of renal blood flow was assessed in vivo in pentobarbital-anesthetized rats using an ultrasonic flow probe placed around the left renal artery. In ANG II-vehicle-treated rats, decreasing arterial pressure over a range from 160 to 100 mmHg resulted in a 25 ± 5% decrease in renal blood flow, demonstrating a significant loss of autoregulation with an autoregulatory index of 0.66 ± 0.15. However, clopidogrel treatment preserved autoregulatory behavior in ANG II-treated rats to levels indistinguishable from normotensive sham-operated (sham) rats (autoregulatory index: 0.04 ± 0.14). Compared with normotensive sham-vehicle-treated rats, ANG II infusion increased renal CD3-positive T cell infiltration by 66 ± 6%, induced significant thickening of the preglomerular vessels and glomerular basement membrane and increased glomerular collagen I deposition, tubulointerstitial fibrosis, damage to the proximal tubular brush border, and protein excretion. Clopidogrel significantly reduced renal infiltration of T cells by 39 ± 9% and prevented interstitial artery thickening, ANG II-induced damage to the glomerular basement membrane, deposition of collagen type I, and tubulointerstitial fibrosis, despite the maintenance of hypertension. These data demonstrate that systemic P2Y12 receptor blockade with clopidogrel protects against impairment of autoregulatory behavior and renal vascular injury in ANG II-induced hypertension, possibly by reducing renal T cell infiltration.

Histopathological and clinical findings in renal transplants with Banff type II and III acute cellular rejection without tubulointerstitial infiltrates

According to the Banff guidelines for renal transplants, pure endothelialitis without any tubulointerstitial infiltrates (with the Banff components v ≥ 1, i0, t0) has to be called acute cellular rejection (ACR). The pathophysiology of this rare lesion abbreviated as v_only is currently unclear, as well as its clinical, serological, and prognostic implications. Therefore, we conducted this retrospective comparative study. We compared all 23 biopsies with v_only from Hannover Medical School between 2003 and 2010 with 23 matched biopsies with the Banff components v ≥ 1, i ≥ 1, and t ≥ 1 (v_plus) and 23 biopsies with v0, i0, and t0 (v0i0t0). Serological (available in 10, 11, and 14 patients, respectively), histological, and clinical data were compared. Of all biopsies, 0.4% had findings of v_only. v_only, v_plus, and v0i0t0 only showed minimal differences in the Banff components apart from the cohort-defining components. Endothelialitis in v_only more frequently involved the arcuate arteries than the smaller preglomerular vessels compared to v_plus and vice versa. Combining histopathological data and serological data, v_only more frequently showed criteria for acute humoral rejection than v0i0t0 (albeit not persistent after the Bonferroni-Holm correction in pairwise comparisons), while there was no difference between v_only and v_plus. No difference could be demonstrated regarding clinical presentation at biopsy or outcome. Our results show minimal differences regarding clinical presentation, outcome, and histological features between v_only and v_plus. Patients with v_only should be thoroughly investigated for evidence of acute humoral rejection.

Control of renin secretion from kidneys with renin cell hyperplasia

In states of loss-of-function mutations of the renin-angiotensin-aldosterone system, kidneys develop a strong hyperplasia of renin-producing cells. Those additional renin cells are located outside the classic juxtaglomerular areas, mainly in the walls of preglomerular vessels and most prominently in multilayers surrounding afferent arterioles. Since the functional behavior of those ectopic renin cells is yet unknown, we aimed to characterize the control of renin secretion from kidneys with renin cell hyperplasia. As a model, we used kidneys from mice lacking aldosterone synthase (AS⁻/⁻ mice), which displayed 10-fold elevations of renin mRNA and plasma renin concentrations. On the absolute level, renin secretion from isolated AS⁻/⁻ kidneys was more than 10-fold increased over wild-type kidneys. On the relative level, the stimulation of renin secretion by the β-adrenergic activator isoproterenol or by lowering of the concentration of extracellular Ca²⁺ was very similar between the two genotypes. In addition, the inhibitory effects of ANG II and of perfusion pressure were similar between the two genotypes. Deletion of connexin40 blunted the pressure dependency of renin secretion and the stimulatory effect of low extracellular Ca²⁺ on renin secretion in the same manner in kidneys of AS⁻/⁻ mice as in wild-type mice. Our findings suggest a high degree of functional similarity between renin cells originating during development and located at different positions in the adult kidney. They also suggest a high similarity in the expression of membrane proteins relevant for the control of renin secretion, such as β₁-adrenergic receptors, ANG II type 1 receptors, and connexin40.

Development of renal renin-expressing cells does not involve PDGF-B-PDGFR-βsignaling

Apart from their endocrine functions renin-expressing cells play an important functional role as mural cells of the developing preglomerular arteriolar vessel tree in the kidney. The recruitment of renin-expressing cells from the mesenchyme to the vessel wall is not well understood. Assuming that it may follow more general lines of pericyte recruitment to endothelial tubes we have now investigated the relevance of the platelet-derived growth factor (PDGF)-B-PDGFR-β signaling pathway in this context. We studied renin expression in kidneys lacking PDGFR-β in these cells and in kidneys with reduced endothelial PDGF-B expression. We found that expression of renin in the kidneys under normal and stimulated conditions was not different from wild-type kidneys. As expected, PDGFR-β immunoreactivity was found in mesangial, adventitial and tubulo-interstitial cells but not in renin-expressing cells. These findings suggest that the PDGF-B-PDGFR-β signaling pathway is not essential for the recruitment of renin-expressing cells to preglomerular vessel walls in the kidney.

Abstract 250: 20-HETE is Increased and EETs are Decreased in the Renal Vasculature of a Rat Model of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among women during their reproductive years. Enlarged ovaries containing numerous small cysts, elevated circulating androgens, modest increases in blood pressure, and insulin resistance, are among the main symptoms of PCOS. However, the mechanisms responsible for higher blood pressure have not been elucidated. We have characterized a rat model of PCOS, the hyperandrogenemic female (HAF) rat that exhibits characteristics of PCOS in women. The present study was performed to test the hypothesis that 20-HETE and EET levels and expression of the cytochrome P450 (CYP) 4A ω-hydroxylases are different in HAF and placebo rats. Dihydrotestosterone (DHT) (7.5 mg/90 days) or placebo pellets were implanted subcutaneously in female SD rats (n = 6/group) at 4 weeks of age. Kidneys were removed at 12 weeks of age, preglomerular vessels isolated, and 20-HETE, EETs, and ω-hydroxylase activity were measured by liquid chromatography-mass spectroscopy; CYP 4A protein was measured by western blot. The basal renal microvascular level of 20-HETE (0.15± 0.02 vs. 0.81± 0.08 pmol/mg; p<0.001) and renal vascular ω-hydroxylase activity (0.20± 0.04 vs. 0.69± 0.14 pmol/min/mg; p<0.01) were higher in HAF compared to placebo controls. In addition, CYP4A protein expression was increased by 79% (0.31 vs. 0.40 AU; p<0.005) in HAF rats. In contrast, the basal renal microvascular level of EETs was reduced in HAF rats (40.80± 11.96 vs. 2.33± 1.74 pmol/mg; p<0.005). The data suggest that renal production of 20-HETE is increased in HAF, and may contribute to renal vascoconstriction, whereas EETs are decreased which may contribute to reduced vasodilation of preglomerular vasculature. These data suggest that androgens may affect intrarenal vascular eicosanoids in women with PCOS to mediate their increases in blood pressure.

Tempol blunts afferent arteriolar remodeling in chronic nitric oxide-deficient hypertension without normalizing blood pressure

Background/Aim: Renal preglomerular vessels play a central role in modulating renal function and injury, especially during conditions of renal hemodynamic stress such as hypertension. We evaluated whether improving the balance between nitric oxide (NO) and oxidative stress improves the morphological alterations of renal afferent arterioles that occur in NO deficiency-induced hypertension.Methods: We measured indices of NO and oxidative stress and evaluated renal morphology and afferent arteriolar remodeling in rats treated with vehicle, L-NAME or L-NAME plus tempol (a superoxide dismutase mimetic) for 6 weeks.Results: L-NAME-treated rats had hypertension, lower urinary and renal NO indices, higher renal cortical levels of TBARS, GSSG and GSSG/GSH. This was associated with significant eutrophic inward remodeling of the afferent arterioles; they had a marked decrease in arteriolar lumen area and a striking increase in arteriolar wall thickness and media to lumen ratio. Tempol did not significantly reduce blood pressure, but increased NO levels, decreased oxidative stress and partially blunted L-NAME-induced remodeling of afferent arterioles.Conclusion: L-NAME-induced remodeling of afferent arterioles is blunted by tempol. This beneficial effect on remodeling is associated with increases in NO indices, decreases in oxidative stress, without significant decreases in blood pressure. Thus, the balance between these components may contribute to the altered renal hemodynamics and function in this model.

Procollagen I-expressing renin cell precursors

Renin-expressing cells in the kidney normally appear as mural cells of developing preglomerular vessels and finally impose as granulated juxtaglomerular cells in adult kidneys. The differentiation of renin-expressing cells from the metanephric mesenchyme in general and the potential role of special precursor stages in particular is not well understood. Therefore, it was the aim of this study to search for renin cell precursors in the kidney. As an experimental model, we used kidneys of aldosterone synthase-deficient mice, which display a prominent compensatory overproduction of renin cells that are arranged in multilayered perivascular cell clusters. We found that the perivascular cell clusters contained two apparently distinct cell types, one staining positive for renin and another one staining positive for type I procollagen (PC1). It appeared as if PC1 and renin expression were inversely related at the cellular level. The proportion of renin-positive to PC1-positive cells in the clusters was inversely linked to the rate of salt intake, as was overall renin expression. Our findings suggest that the cells in the perivascular cell clusters can reversibly switch between PC1 and renin expression and that PC1-expressing cells might be precursors of renin cells. A few of those PC1-positive cells were found also in adult wild-type kidneys in the juxtaglomerular lacis cell area, in which renin expression can be induced on demand.

The aldo-keto reductase AKR1B7 coexpresses with renin without influencing renin production and secretion

On the basis of evidence that within the adult kidney, the aldo-keto reductase AKR1B7 (aldo-keto reductase family 1, member 7, also known as mouse vas deferens protein, MVDP) is selectively expressed in renin-producing cells, we aimed to define a possible role of AKR1B7 for the regulation and function of renin cells in the kidney. We could confirm colocalization and corecruitment of renin and of AKR1B7 in wild-type kidneys. Renin cells in AKR1B7-deficient kidneys showed normal morphology, numbers, and intrarenal distribution. Plasma renin concentration (PRC) and renin mRNA levels of AKR1B7-deficient mice were normal at standard chow and were lowered by a high-salt diet directly comparable to wild-type mice. Treatment with a low-salt diet in combination with an angiotensin-converting enzyme inhibitor strongly increased PRC and renin mRNA in a similar fashion both in AKR1B7-deficient and wild-type mice. Under this condition, we also observed a strong retrograde recruitment of renin-expressing cell along the preglomerular vessels, however, without a difference between AKR1B7-deficient and wild-type mice. The isolated perfused mouse kidney model was used to study the acute regulation of renin secretion by ANG II and by perfusion pressure. Regarding these parameters, no differences were observed between AKR1B7-deficient and wild-type kidneys. In summary, our data suggest that AKR1B7 is not of major relevance for the regulation of renin production and secretion in spite of its striking coregulation with renin expression.

Endothelium-Derived Nitric Oxide Supports Renin Cell Recruitment Through the Nitric Oxide–Sensitive Guanylate Cyclase Pathway

Chronic challenge of renin-angiotensin causes recruitment of renin-producing cells in the kidney along the media layer of afferent arterioles and hypertrophy of cells in the juxtaglomerular apparatus. This study aimed to define the role of nitric oxide (NO) with regard to the recruitment pattern of renin-producing cells and to the possible pathways along which NO could act. We considered the hypothesis that endothelium-derived NO acts via NO-sensitive guanylate cyclase. Mice were treated with low-salt diet in combination with the angiotensin I-converting enzyme inhibitor enalapril for 3 weeks, which led to a 13-fold increase in renin expression associated with marked recruitment of renin cells in afferent arterioles and hypertrophy of the juxtaglomerular apparatus in wild-type mice. In wild-type mice additionally treated with the nonselective NO synthase inhibitor L-NAME, the recruitment of renin-expressing cells along the afferent arterioles was absent and juxtaglomerular hypertrophy was diminished. An almost identical attenuation of renin cell recruitment as with L-NAME treatment in wild-type mice was found in mice lacking the endothelial isoform of NO synthase. Treatment of mice lacking NO-sensitive guanylate cyclase in renin-expressing cells and preglomerular smooth muscle cells with low-salt diet in combination with the angiotensin I-converting enzyme inhibitor enalapril for 3 weeks produced juxtaglomerular hypertrophy like in wild-type mice, but no recruitment in afferent arterioles. These findings suggest that endothelium-derived NO and concomitant formation of cGMP in preglomerular renin cell precursors supports recruitment of renin-expressing cells along preglomerular vessels, but not in the juxtaglomerular apparatus.

Nitric Oxide Can Directly Mediate Renin Cell Recruitment

See related article, pp 400–407 In this issue of Hypertension , Neubauer et al1 fit missing pieces into the puzzle of how renin production is controlled, when the demand for renin is high. Our understanding of the acute release of renin is much more complete than what we know about the long-term adaptations to stimuli of renin. Our scarce knowledge of the mechanisms mediating long-term renin stimulation is remarkable with regard to the clinical importance of renin. Hypertension, fluid and electrolyte homeostasis, as well as inflammation and fibrosis all may involve chronic renin stimulation.2 More than 400 million years ago, renin first appeared in organisms,3 and renin is often seen as the first hormone discovered. Shortly before the 20th century, Tigerstedt and Bergman showed that kidney extracts can elevate blood pressure, when intravenously infused.4 Today, we recognize that the actions of renin go far beyond that of controlling blood pressure, and we have detailed insight into how renin is released into the circulation.5 The major stimuli of short-term renin release are blood pressure decreases, β1-adrenergic stimulation, and low salt, whereas …

Systematic Histological Analysis of Thrombotic Microangiopathy in a Porcine Xeno-Kidney-Transplant-Model

Introduction: Despite a variety of pharmacologic and transgenic interventions thrombotic microangiopathy is still a big challenge in porcine to human xenotransplantion. A detailed molecular analysis of histological patterns in xenokidneytransplant-models is necessary for a targeted anticoagulant therapy and a better understanding of the pathophysiology of human transplant associated thrombotic microangiopathy. Methods: Porcine kidneys were perfused with human whole blood (n=5). The histological alterations as well as the function of these kidneys were analysed in different intervention groups (application of antithrombin and activated Protein C (aPC), each n=5) and controls (perfusion with porcine whole blood, n=4). Microthrombi positive for fibrin (Fib+MT) and activated platelets (CD61+MT) were defined as lumen occlusion of more than 50% with fibrin and activated platelets. 100 glomeruli and preglomerular vessels per sample were analyzed. Results: Preglomerular CD61+MT were diminished in xenotransplants after application of aPC and antithrombin. Glomerular CD61+MT were increased in xenotransplants with and without intervention compared to controls. Only aPC, but not antithrombin was able to significantly diminish glomerular CD61+MT in xenotransplants. There were no differences in glomerular and preglomerular Fib+MT between both intervention groups. In total CD61+MT were more frequently observed than Fib+MT. Conclusion: Microthrombi in xenotransplants seem to be composed predominantly of platelets. In dependence on different antithrombotic interventions the number of microthrombi is diminished and the ratio of Fib+MT compared to CD61+MT is altered. Underlying mechanisms and the role of the vessel wall will be further investigated by gene expression analysis of pro- and antithrombotic factors. These data will be correlated with histological and laboratory data. These data will hopefully guide targeted antithrombotic interventions.

Endothelialitis without Tubulointerstitial Infiltrates in Renal Transplant Biopsies: Histological Findings, Clinical and Prognostic Relavance

Introduction: In order to avoid unnecessary therapy it is currently debated, whether acute cellular rejection with Banff components v≥1, i0, t0 (v_only) has the same therapeutic and prognostic implications as acute cellular rejections with Banff components v≥1, i≥1, t≥1 (v_plus). We examined this question retrospectively in renal transplant biopsies from a single center. Methods: All 23 renal transplant biopsies (from 23 patients) from our biopsy archive with v_only were retrospectively compared to 23 biopsies from 23 patients with v_plus. All patients, v_only and v_plus, received therapy for acute cellular rejection. They were then followed for 135 weeks ±106 (v_only) or 201 weeks ± 151 (v_plus). Results: No significant difference was found between v_only and v_plus regarding donor sex, donor age, immunosuppressive regimen, recipient age, time between transplantation and biopsy, number of glomeruli in the biopsy, Banff components v, g, mm, ah, cg, cv, ci, ptc, ratio of of preglomerular vessels with endothelialits to sum of preglomerular vessels, C4d-positivity of preglomerular endothelium, of peritubular capillary endothelium (Banff C4d), of glomerular endothelium, eGFR at biopsy, type of anti-rejection therapy, eGFR one week after initiation of anti-rejection therapy, eGFR slope per week between biopsy and end of follow-up.v_only had significantly more HLA-mismatches, a higher Banff ct component and and less cortical tubular interstitial edema. Conclusion: Our data show marginal histological differences between v_only and v_plus (with the exception of the defining Banff components i and t). We could not find a difference regarding response to anti-rejection therapy, transplant function or prognosis between v_plus and v_only. The higher number of HLA-mismatches in v_only might suggest, that this rare diagnosis could be associated with donor specific antibodies. We will examine this possible association further in our cohort.