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Effects of selective and non-selective NOS inhibitors on morphological changes in the renal ischemic outer medulla. Effect of nonspecific NOS inhibitor (L-NAME), iNOS inhibitor (1400W) and nNOS inhibitor (NPLA) on morphological changes (necrosis, casts, congestion and inflammation) in the renal ischemic outer medulla.
Source publication
Ischemic acute kidney injury (iAKI) in experimental diabetes mellitus (DM) is associated with a rapid kidney dysfunction more than in non-diabetic rats. We hypothesize that this vulnerability is due to excessive endothelin-1 (ET-1) expression along with dysregulation of nitric oxide synthase (NOS) isoforms. The aim of the present study was to asses...
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Administration of the mineralocorticoid receptor antagonist spironolactone prevents the development of chronic kidney disease (CKD) after a severe ischemic injury. However, whether brief periods of ischemia lead to CKD and whether spironolactone administration after ischemia may be a useful therapeutic strategy to prevent the gradual deterioration...
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Aims:
Endothelin-1 levels are raised in chronic thromboembolic pulmonary hypertension. Our aim in this study was to identify the presence of endothelin receptors in patients with CTEPH by analysing tissue removed at pulmonary endarterectomy.
Main methods:
Pulmonary endarterectomy tissue cross-sections were analysed using autoradiography with [(1...
Endothelin-1 (ET-1) acts on ET(A) and ET(B) receptors and has been implicated in hemorrhagic shock (shock). We determined effect of shock and resuscitation by hypertonic saline (saline) or centhaquin on ET(A) and ET(B) receptor expression. Rats were anesthetized, a pressure catheter was placed in the left femoral artery; blood was withdrawn from th...
Citations
... Previously, DM was proven to be a risk factor for AKI after minimally invasive partial nephrectomy, especially when the preoperative hemoglobin A1c level was > 7% [10]. In the experimental studies, the diabetic kidney showed more deleterious renal function after renal I/R injury than the non-diabetic kidney, and this vulnerability was due to enhanced endothelin-1 production and upregulation of harmful inducible NOS [27]. Moreover, impaired autophagic response in the kidney and induction of a stress response gene p53 were involved in the susceptibility Fig. 4 The probability of acute kidney injury (AKI) based on the risk scoring system of the diabetic kidney to renal I/R [28,29]. ...
Background
Acute kidney injury after partial or radical nephrectomy remains an unsolved problem even when using minimally invasive techniques. We aimed to identify risk factors for acute kidney injury (AKI) after minimally invasive nephrectomy and to develop a clinical risk scoring system.
Methods
Medical records of 1762 patients who underwent minimally invasive laparoscopic or robot-assisted laparoscopic partial (n = 1009) or radical (n = 753) nephrectomy from December 2005 to November 2018 were reviewed. Candidate risk factors were screened using univariate analysis and ranked using linear discriminant analysis; top ranking factors were incorporated into a multivariate logistic regression model. Then, the final clinical scoring system was created based on the estimated odds ratios.
Results
The incidence of acute kidney injury after partial or radical nephrectomy was 20.3 and 61.6%, respectively. Risk factors incorporated into the scoring system included: size of the parenchymal mass removed (3 < parenchymal mass ≤ 4 cm, 1 point; 4 < parenchymal mass ≤ 6 cm, 3 points; parenchymal mass > 6 cm, 5 points), male sex (2 points), diabetes mellitus (1 point), warm ischemia time ≥ 25 min (1 point), and immediate postoperative neutrophil count ≥ 12,000 µl⁻¹ (1 point) in patients with partial nephrectomy, and sex (male, 10 points; female, 7 points) in patients with radical nephrectomy. For risk scores of 0–4, 5–6, 7, 8–9, and 10 points, the probabilities of acute kidney injury were approximately 10, 20, 40, 60, and 80%, respectively. The predictive accuracy of the scoring system was 0.827 (95% CI 0.789–0.865).
Conclusion
Our risk scoring system could help clinicians identify those at risk of acute kidney injury after minimally invasive partial or radical nephrectomy, thereby optimizing postoperative management.
... Moreover, 6-h restraint stress produces inflammation, which is proved by statistically significant increase of IL-1β and C-reactive protein concentrations as a hallmark of the acute phase response. The CRP, in turn, is able to activate iNOS [11,12]. It was shown that C-reactive protein activates monocytes [12], which produces proinflammatory cytokines with subsequent iNOS activation and potentiation of inflammatory response. ...
... Other mechanisms of skeletal muscle I/R injury have been investigated [13,14]. Many studies [15][16][17] have reported that endothelial dysfunction resulting from an imbalance of vasoactive substances, including endothelin 1 (ET-1), as well as neuronal and endothelial nitric oxide synthases (nNOS and eNOS) plays a role in the pathophysiology of several ischemic conditions. Concordantly, ET-1, nNOS, and eNOS are involved in skeletal muscle I/R. ...
Ischemia and reperfusion (I/R) injury induced by tourniquet (TQ) application leads to the release of both oxygen free radicals and inflammatory cytokines. The skeletal muscle I/R may contribute to local skeletal muscle and remote organ damage affecting outcomes after total knee arthroplasty (TKA). The aim of the study is to summarize the current findings associated with I/R injury following TKA using a thigh TQ, which include cellular alterations and protective therapeutic interventions. The PubMed database was searched using the keywords “ischemia reperfusion injury,” “oxidative stress,” “tourniquet,” and “knee arthroplasty.” The search was limited to research articles published in the English language. Twenty-eight clinical studies were included in this qualitative review. Skeletal muscle I/R reduces protein synthesis, increases protein degradation, and upregulates genes in cell stress pathways. The I/R of the lower extremity elevates local and systemic oxidative stress as well as inflammatory reactions and impairs renal function. Propofol reduces oxidative injury in this I/R model. Ischemic preconditioning (IPC) and vitamin C may prevent oxygen free radical production. However, a high dose of N -acetylcysteine possibly induces kidney injury. In summary, TQ-related I/R during TKA leads to muscle protein metabolism alteration, endothelial dysfunction, oxidative stress, inflammatory response, and renal function disturbance. Propofol, IPC, and vitamin C show protective effects on oxidative and inflammatory markers. However, a relationship between biochemical parameters and postoperative clinical outcomes has not been validated.
... Abu-Saleh et al. (23) in a diabetic rat model induced with STZ identified histological changes in both diabetic and nondiabetic rats after 30 min renal ischaemia and reported that for all pathological parameters, including congestion and inflammation in the interior of diabetic ischaemic renal medulla, the morphologic score was 2.5 times higher. Our study identified a significant increase in proximal tubular injury in both diabetic sham and diabetic IR groups compared to the nondiabetic group. ...
Objective:
The aim of this study was to investigate the effects of dexmedetomidine before and after ischaemia in diabetic rat kidney ischaemia reperfusion (IR) injury in the experimental diabetic rat model.
Methods:
Data belonging to 35 rats weighing between 250 and 300 g were analysed. Diabetes mellitus (DM) was induced using streptozotocin. Groups had bilateral renal vasculature clamped for 45 min ischaemia before clamps were removed, and 4 hours reperfusion was applied. Rats were divided into five groups: Group I or nondiabetic sham group (n=7), Group II or diabetic sham group (n=7), Group III or diabetic IR group (n=7), Group IV or diabetic IR+prophylactic Dex P (before ischaemia) (n=7) and Group V or diabetic IR+therapeutic Dex T (following reperfusion) (n=7). Dexmedetomidine was administered at a dose of 100 μg kg-1 intraperitoneally. Histomorphological and biochemical methods were used to assess the blood and tissue samples.
Results:
The proximal tubule injury score in the control sham group was significantly lower than in other groups. The proximal tubule and total cell damage scores of the diabetic IR group were significantly higher than the diabetic IR+Dex T group, and no significant difference was detected in the diabetic IR+Dex P group. The biochemical parameters of the IR group were significantly increased compared to Groups I and II; however, there was no significant reduction in these parameters in the groups administered dexmedetomidine.
Conclusion:
Although administration of dexmedetomidine after ischaemia in the diabetic rat renal IR model was found to be more effective on the histopathological injury scores compared to preischaemic administration, this study has not shown that dexmedetomidine provides effective and complete protection in DM.
... Выявленное нами и другими исследователями [5] системное воспаление низкой интенсивности, развивающееся при хронической гипергликемии, объясняет частое возникновение при этом сосудистых «катастроф», важнейшим звеном патогенеза ЛазукО С. С. ...
... Thus, preventing renal I/R injury in DM by investigating possible protective strategies is clinically important. Abu-Saleh et al. [20] in a diabetic rat model induced with streptozotocin identified histological changes in both diabetic and nondiabetic rats after 30 minutes of renal ischemia. They reported a broader pattern of injury in the diabetic ischemic kidney noted in the inner stripe of the outer medulla, including also congestion and inflammation, with all pathological parameters higher than 2.5 in morphological score. ...
Background:
The aim of this study was to evaluate the effects of local ischemic preconditioning using biochemical markers and histopathologically in the diabetic rat renal IR injury model.
Methods:
DM was induced using streptozotocin. Rats were divided into four groups: Group I, nondiabetic sham group (n = 7), Group II, diabetic sham group (n = 6), Group III, diabetic IR group (diabetic IR group, n = 6), and Group IV, diabetic IR + local ischemic preconditioning group (diabetic IR + LIPC group, n = 6). Ischemic renal injury was induced by clamping the bilateral renal artery for 45 min. 4 h following ischemia, clearance protocols were applied to assess biochemical markers and histopathologically in rat kidneys.
Results:
The histomorphologic total cell injury scores of the nondiabetic sham group were significantly lower than diabetic sham, diabetic IR, and diabetic IR + LIPC groups. Diabetic IR group scores were not significantly different than the diabetic sham group. But diabetic IR + LIPC group scores were significantly higher than the diabetic sham and diabetic IR groups.
Conclusion:
Local ischemic preconditioning does not reduce the risk of renal injury induced by ischemia/reperfusion in diabetic rat model.
... However, data are conflicting. At least five studies have shown that ET-1 receptor blockade either conferred no functional protection, or worsened post-ischemic AKI [36][37][38][39][40]. In a more recent ischemia-reperfusion model in mice undergoing unilateral ischemia without contralateral nephrectomy, an increase in intrarenal ET-1 production was observed, along with increased expression of the ET A receptor and evidence of ET-1 gene activation alongside progressive histological changes and a 40% loss of renal mass [41]. ...
Renal disease is a global phenomenon with the incidence of both acute and chronic renal insufficiency continuing to rise [1, 2]. Acute kidney injury (AKI) is a known independent predictor of hospital mortality despite its multifactorial nature. After an episode of AKI, there are four potential outcomes [3]:
It was previously assumed that those who recovered kidney function after an episode of AKI were faced with a relatively benign course with favorable outcomes. However, there is now increasing concern that this is not neccesarily the case and these individuals may be at risk of poor long-term outcomes through the development of CKD (including ESRF), further episodes of AKI and an increased risk of premature death. In the following review, we will describe the main pathogenetic links between AKI and CKD and introduce some potential key players.
... ET-1 plays an important role in cell proliferation, podocyte dysfunction, extracellular matrix remodeling, inflammation and renal fibrosis, and, arguably, these effects may be more significant in the progression of chronic kidney diseases than its prohypertensive activities [8]. Chronic infusion of exogenous ET-1 was found to increase glomerular permeability to albumin, but has no action on proteinuria [1]. Schildroth et al. [25] note that ET-1 increases vascular resistance and the decrease in blood flow contributes to renal tissue dysfunction. ...
... Also previous experiments carried out on animals provide evidence that increased activation of NF-κB increases the expression of ET-1 in the pulmonary arteries [31], blood, liver [20], and kidney [28]. In the kidney, overexpression of ET-1 has been implicated in the pathogenesis of many kidney diseases, suggesting a role in kidney injury [1,34]. ...
Aim:
The aim of the study was to evaluate the effect of BAY 11-7082, an NF-κB inhibitor, on basal and ET-1-induced production of reactive oxygen species (ROS), TNF-α and p65 protein in rat kidney.
Material/methods:
The experimental animals were divided into five groups (n=7) receiving: 1) saline (control); 2 and 3) ET-1 in a dose of 3 μg/kg body weight (b.w.) or 12.5 μg/kg b.w.; 4) BAY 11-7082 (10 mg/kg b.w.); 5) BAY 11-7082 (10 mg/kg b.w.) and ET-1 (12.5 μg/kg b.w.), respectively. In kidney homogenates the concentration of thiobarbituric acid reactive substances (TBARS), H2O2, TNF-α, p65 protein and GSH/GSSG ratio were determined.
Results:
ET-1 resulted in a dose-dependent increase in TBARS and hydrogen peroxide (H2O2) levels, and a decrease in GSH/GSSG ratio when compared to the controls. BAY 11-7082 administered 1 h before ET-1 administration at a dose of 12.5 μg/kg resulted in a decrease (P<0.001) in TBARS and H2O2 levels and an increase (P<0.001) in GSH/GSSG ratio compared to the ET-1 groups. The level of TNF-α was increased (P<0.001) in the presence of ET-1, while BAY 11-7082 reduced the TNF-α level (P<0.001). The rats receiving BAY 11-7082 showed a decrease in NF-κB p65 protein level in the nuclear fraction and an increase in the cytoplasmic fraction.
Conclusions:
The results suggest that BAY 11-7082 plays a protective role against ET-1 induced oxidative stress in kidney tissue. These actions of BAY 11-7082 may result from reduced activity of NF-κB signaling pathways. Inhibition of the NF-κB pathway may be a promising strategy for preventing the progression of kidney damage.
... The vasodilatory action of tadalafil is of a special importance in light of the intrarenal activation of vasoconstrictory systems (endothelin, adenosine and angiotensin II) that contribute to reduction in GFR, together with vascular congestion in the outer medulla and activation of tubuloglomerular feedback during AKI. Moreover, we and others have shown that renal I/R injury is characterized by downregulation of eNOS and upregulation of iNOS [28]. While eNOS-derived NO plays a pivotal protective role in I/R-induced acute renal failure, iNOS adversely affects renal function/structure [28]. ...
... Moreover, we and others have shown that renal I/R injury is characterized by downregulation of eNOS and upregulation of iNOS [28]. While eNOS-derived NO plays a pivotal protective role in I/R-induced acute renal failure, iNOS adversely affects renal function/structure [28]. Using a similar AKI model, Choi et al. [29] have demonstrated that sildenafil significantly enhanced iNOS and eNOS in the renal tissue of I/R rats compared with controls. ...
Interruption of renal blood flow is often necessary during nephron sparing surgery (NSS) and can induce renal injury. This study examines whether tadalafil, a phosphodiesterase-5 (PDE-5) inhibitor and well-known vasodilator, exerts nephroprotective effects in patients undergoing NSS.
This non-randomized study included 49 patients with enhancing solid renal mass. All patients were subjected to open NSS during which clamping the renal artery was performed. Twenty-two patients were pretreated with tadalafil 1 day prior NSS and 2 days following surgery. The other 27 patients underwent the same surgical procedure but did not receive tadalafil (controls). Urine samples were collected before surgery and following renal pedicle clamp removal. Urine levels of NGAL and KIM-1, two novel biomarkers for acute kidney injury (AKI), were determined.
Clamping the renal artery induced kidney dysfunction as reflected by increases in urinary NGAL and KIM-1 in all participants. These increases in urinary NGAL and KIM-1 excretion were evident 1 h after renal ischemia and lasted for 72 and 24 h, respectively. Pretreatment with tadalafil reduced the absolute urinary excretion of KIM-1, but not of NGAL. Although the incidence of AKI was comparable between tadalafil-treated and untreated NSS subjects, the elevation in serum creatinine (SCr) was significantly attenuated in tadalafil-treated group as compared with NSS controls.
Tadalafil exerts nephroprotective effects in AKI following NSS, as was evident by reduced urinary excretion of KIM-1 and attenuation of SCr elevation. Carefully controlled large clinical studies are needed before defining the role of PDE-5 inhibition therapy in these patients.
... Endothelial dysfunction is a major contributor to ischemic renal damage and is characterized by an imbalance between the release of ET-1 and nitric oxide (NO). 22 Damage to vascular endothelial cells during reperfusion may lead to the release of ET from injured endothelial cells, followed by sustained intrarenal vasoconstriction and thus hypoxic injury of the adjacent tubules. 8,23 In diabetes, these events may be even more pronounced because insulin resistance results in widespread endothelial dysfunction with increased levels of ET-1 and decreases in NO through disruption of NO synthase. ...
... This further impairs renal vascular autoregulation. 22 In rats treated with streptozotocin, IRI led to a more severe renal phenotype than in nondiabetic animals. With the use of selective ET A blockers, a partial improvement of kidney function in diabetic rats that underwent IRI was observed. ...
... With the use of selective ET A blockers, a partial improvement of kidney function in diabetic rats that underwent IRI was observed. 22 RNA interference with a short hairpin RNA for ET A partially silenced gene expression and led to improved renal function and structure in IRI injury in rats 24 (Table 1). ...
All components of the endothelin (ET) system are present in renal tubular cells. In this review, we summarize current knowledge about ET and the most common tubular diseases: acute kidney injury (AKI) and polycystic kidney disease. AKI originally was called acute tubular necrosis, pointing to the most prominent morphologic findings. Similarly, cysts in polycystic kidney disease, and especially in autosomal-dominant polycystic kidney disease, are of tubular origin. Preclinical studies have indicated that the ET system and particularly ETA receptors are involved in the pathogenesis of ischemia-reperfusion injury, although these findings have not been translated to clinical studies. The ET system also has been implicated in radiocontrast-dye-induced AKI, however, ET-receptor blockade in a large human study was not successful. The ET system is activated in sepsis models of AKI; the effectiveness of ET blocking agents in preclinical studies is variable depending on the model and the ET-receptor antagonist used. Numerous studies have shown that the ET system plays an important role in the complex pathophysiology associated with cyst formation and disease progression in polycystic kidney disease. However, results from selective targeting of ET-receptor subtypes in animal models of polycystic kidney disease have proved disappointing and do not support clinical trials. These studies have shown that a critical balance between ETA and ETB receptor action is necessary to maintain structure and function in the cystic kidney. In summary, ETs have been implicated in the pathogenesis of several renal tubulointerstitial diseases, however, experimental animal findings have not yet led to use of ET blockers in human beings.
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