Angiotensin II and endothelin induce inflammation and thereby promote hypertension-induced end-organ damage

Angiotensin (Ang) II and endothelin (ET-1) can both be regulated by NF-kappaB. They are, to variable degrees, also capable of activating NF-kappaB and increase the expression of NF-kappaB-dependent genes. Ang II-related vascular effects are in part mediated by ET-1. Nitric oxide synthase inhibition facilitates Ang II-related effects, which can be inhibited both by AT1-receptor blockers and by endothelin system inhibitors. This state-of-affairs supports the notion that a combined therapeutic strategy of inhibiting Ang II and ET-1 generation or blocking their effects at the receptor level would be superior to either strategy alone. Animal studies are encouraging but not without conflicting results. Angiotensin-converting enzyme inhibitors and AT1-receptor blockers have a superb track record in experimental animal models and in a host of clinical studies. Selective and nonselective blockers of the ET-1 receptors are important research tools and are also undergoing clinical trials. Inhibitors of the endothelin-converting enzyme have been developed. The recent elucidation of the endothelin-converting enzyme's physical structure should facilitate the development of still more novel compounds to inhibit ET-1 generation. We have recently engendered supportive evidence in this regard.     

Hypertonic saline attenuates end-organ damage in an experimental model of acute pancreatitis

BACKGROUND: Hypertonic saline (HTS) has been noted previously to reduce neutrophil activation. The aim of this study was to elucidate the effect of hypertonic resuscitation on the development of end-organ damage in an animal model of pancreatitis. METHODS: Pancreatitis was induced in Sprague-Dawley rats by intraperitoneal injection of 20 per cent L-arginine. Animals were randomized into four groups (each n = 8): controls; pancreatitis without intervention; pancreatitis plus intravenous resuscitation with normal saline (0.9 per cent sodium chloride 2 ml/kg) at 24 and 48 h; or HTS (7.5 per cent sodium chloride 2 ml/kg) at these time points. Pulmonary endothelial leakage was assessed by measurement of lung wet : dry ratios, bronchoalveolar lavage protein and myeloperoxidase activity. RESULTS: Animals that received HTS showed less pancreatic damage than those resuscitated with normal saline (1.0 versus 3.0; P = 0.04). Lung injury scores were also significantly diminished in the HTS group (1.0 versus 3.5; P = 0.03). Pulmonary neutrophil sequestration (myeloperoxidase activity 1.80 units/g) and increased endothelial permeability (bronchoalveolar lavage protein content 1287 microgram/ml) were evident in animals resuscitated with normal saline compared with HTS (1.22 units/g and 277 microgram/ml respectively; P < 0.02). CONCLUSION: HTS resuscitation results in a significant attenuation of end-organ injury following a systemic inflammatory response to severe pancreatitis.     

Blockade of endothelin receptors attenuates end-organ damage in homozygous hypertensive ren-2 transgenic rats

BACKGROUND/AIMS: A growing body of evidence suggests that the interplay between the endothelin (ET) and the renin-angiotensin systems (RAS) plays an important role in the development of the malignant phase of hypertension. The present study was performed to evaluate the role of an interaction between ET and RAS in the development of hypertension and hypertension-associated end-organ damage in homozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGRs) under conditions of normal-salt (NS, 0.45% NaCl) and high-salt (HS, 2% NaCl) intake. METHODS: Twenty-eight-day-old homozygous male TGRs and age-matched transgene-negative male normotensive Hannover Sprague-Dawley (HanSD) rats were randomly assigned to groups with NS or HS intake. Nonselective ET(A/B) receptor blockade was achieved with bosentan (100 mg/kg/day). Systolic blood pressure (BP) was measured in conscious animals by tail plethysmography. Rats were placed into metabolic cages to determine proteinuria and clearance of endogenous creatinine. At the end of the experiment the final arterial BP was measured directly in anesthetized rats. Kidneys were taken for morphological examination. RESULTS: All male HanSD fed either the NS or HS diet exhibited a 100% survival rate until 180 days of age (end of experiment). The survival rate in untreated homozygous male TGRs fed the NS diet was 41%, which was markedly improved by treatment with bosentan to 88%. The HS diet reduced the survival rate in homozygous male TGRs to 10%. The survival rate in homozygous male TGRs on the HS diet was significantly improved by bosentan to 69%. Treatment with bosentan did not influence either the course of hypertension or the final levels of BP in any of the experimental groups of HanSD rats or TGRs. Although the ET-1 content in the renal cortex did not differ between HanSD rats and TGRs, ET-1 in the left heart ventricle of TGRs fed the HS diet was significantly higher compared with all other groups. Administration of bosentan to homozygous male TGRs fed either the NS or HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR. CONCLUSIONS: Our data show that nonselective ET(A/B) receptor blockade markedly improves the survival rate and ameliorates end-organ damage in homozygous male TGRs without significantly lowering BP.     

Endothelial dysfunction in chronic kidney disease: determinant of susceptibility to end-organ damage and therapeutic response

Endothelial dysfunction (ED) seems to be a crucial mediator of increased cardiovascular risk observed among patients with chronic kidney disease (CKD). Importantly, systemic ED does not only occur in patients with severe renal failure, but also in individuals with earlier stages of CKD. Close association between microalbuminuria and systemic ED renders renal vascular function an important marker for the severity of cardiovascular damage. Furthermore, changes in renal endothelium might be actively involved in the progression of renal end-organ damage. Recently, experimental evidence showed that interindividual variability in endothelial function of healthy rats predicts susceptibility to renal damage and the efficacy of renoprotective treatment. Therefore, a specific manipulation of renal and systemic ED might provide benefits in various stages of CKD. ED thus may represent an ideal therapeutic target not only for treatment, but also for primary prevention of renal disease.     

Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene

A sexual dimorphism in hypertension has been observed in both human and laboratory animal studies. The mechanisms by which male sex hormones regulate cardiovascular homeostasis are still not yet fully understood and represent the subject of this study. The possible involvement of androgen receptors in the development of hypertension and end-organ damage in transgenic rats harboring the mouse Ren-2 renin gene [TGR(mREN2)27] was studied. Male TGR(mREN2)27 rats were treated with the androgen receptor antagonist Flutamide starting at 4 wk of age. Also, an androgen receptor mutation (testicular feminization mutation [tfm]) was introduced in these rats by crossbreeding male TGR(mREN2)27 rats with tfm rats. The resulting offspring male rats that contain the tfm mutation are insensitive to androgens. Flutamide treatment or tfm mutation produced a significant attenuation of the development of hypertension. Besides a reduction in cardiac hypertrophy, urinary albumin excretion was blunted and no histologic characteristics of end-organ damage were observed in the kidney after Flutamide treatment. Testosterone levels increased 15-fold after Flutamide treatment and 2.7-fold by the tfm mutation. Also, plasma estrogens and luteinizing and follicle-stimulating hormones were significantly increased. Plasma renin concentrations and activity but not plasma angiotensinogen were reduced. Our results indicate that androgens contribute not only to the development of hypertension, but even more importantly to end-organ damage in TGR(mREN2)27 rats.     

醛固酮与肾脏纤维化

本文综述ALD及醛固酮受体拮抗剂对肾脏纤维化影响的研究进展.     

Rapid development of severe end-organ damage in C57BL/6 mice by combining DOCA salt and angiotensin II

The C57BL/6 mouse strain serves as the genetic background of many transgenic and gene knockout models; however, this strain appears to be resistant to hypertension-induced renal injury. We developed a new model of hypertensive end-organ damage in C57BL/6 mice by combining deoxycorticosterone acetate (DOCA) and salt with angiotensin II infusion. The systolic blood pressure (SBP) was significantly elevated in DOCA salt-angiotensin II mice compared to control mice or mice treated individually with DOCA salt or angiotensin II. Hypertensive glomerular damage, increased expression of profibrotic and inflammatory genes, albuminuria, tubular casts, increased plasma cholesterol, cardiac hypertrophy, and fibrosis were found in mice treated with DOCA salt-angiotensin II. The SBP in the angiotensin II-infused group was further increased by increasing the infusion rate; only mild injury was observed in these mice, suggesting that blood pressure was not a causal factor. Removal of DOCA and the angiotensin pump lowered blood pressure to normal; however, albuminuria along with the glomerular and cardiac damage did not completely resolve. Our study describes a new model of hypertensive end-organ damage and repair in C57BL/6 mice.     

Aldosterone and glomerular podocyte injury

Aldosterone is traditionally viewed as a hormone regulating electrolyte and blood pressure homeostasis by acting on the distal nephron. Accumulating evidence suggests that aldosterone also plays pathogenetic roles in cardiovascular and renal injury. For example, aldosterone is a potent inducer of proteinuria. We demonstrated that podocyte injury underlies the pathogenesis of proteinuria in aldosterone-infused rats on a high salt diet. Mineralocorticoid receptor was detected in the podocytes in vivo and in vitro, and aldosterone caused induction of its effector kinase Sgk1, activation of NADPH oxidase and generation of reactive oxygen species. Selective aldosterone blocker eplerenone, as well as antioxidant tempol, ameliorated aldosterone-induced podocyte injury and proteinuria. Aldosterone was also involved in the podocyte damage and proteinuria of metabolic syndrome model SHR/NDmcr-cp. Adipocyte-derived aldosterone releasing factors were suggested to contribute to the aldosterone excess of this model. Furthermore, high salt diet markedly worsened the renal injury of SHR/NDmcr-cp. Although salt lowered serum aldosterone levels, it caused MR activation in the kidney. Accordingly, eplerenone dramatically improved the salt-evoked nephropathy. Taken together, aldosterone blockers can be an excellent therapeutic strategy for the treatment of podocyte injury, proteinuria, and cardiovascular and renal complications, not only in high aldosterone states but also in patients with activated MR signaling in the target tissue, whose circulating aldosterone level is not necessarily high. Addition of aldosterone blockers in patients treated with ACEIs or ARBs are also promising, because of "aldosterone breakthrough" phenomenon. Careful monitoring of hyperkalemia is necessary, especially in patients with impaired renal function.     

Pharmacogenomics and end-organ susceptibility to injury in the perioperative period

Genomic medicine has provided new mechanistic understanding for many complex diseases over the last 5-10 years. More recently genomic approaches have been applied to the perioperative paradigm, facilitating identification of patients at high risk for adverse events, as well as those who will respond better/worse to specific pharmacologic therapies. The consistent biological theme emerging is that while inflammation is important in healing from surgical trauma, patients who are too robustly proinflammatory appear to be at higher risk for adverse perioperative events. Precise predictors of each adverse event are being elucidated so that corrective therapeutics can be instituted to improve outcomes in high-risk patients. While the field of perioperative genomics could be considered in its infancy, such approaches are the wave of the future.     

Aldosterone and progression of renal disease

PURPOSE OF REVIEW: The aim of this review is to look at the role of aldosterone in the progression of chronic kidney disease. The reduction of blood pressure and proteinuria in patients suffering from chronic kidney disease decreases the rate of disease progression. Suppression of angiotensin formation by angiotensin converting enzyme inhibitors and blockade of the angiotensin II receptor by angiotensin II type 1 antagonists are powerful therapeutic strategies that effectively lower blood pressure and slow the progression of renal disease. These therapies, however, provide only imperfect protection, since they cannot always prevent endstage renal failure. RECENT FINDINGS: Aldosterone plays a significant role in the pathogenesis of arterial hypertension and renal disease. Angiotensin converting enzyme inhibitors and angiotensin II type 1 antagonists are incomplete in suppressing aldosterone production and 'aldosterone breakthrough' can be observed under continued treatment. Aldosterone blockade reduces blood pressure in virtually all patients with hypertension. In proteinuric patients, the addition of an aldosterone antagonist to an angiotensin converting enzyme inhibitor or to angiotensin II type 1 antagonists reduces proteinuria. SUMMARY: The use of aldosterone antagonists in addition to either angiotensin converting enzyme inhibitors or angiotensin II type 1 antagonists in proteinuric patients reduces proteinuria, which may translate into preservation of the glomerular filtration rate in the longer term. Therefore, blockade of the aldosterone pathway may prove to be a beneficial therapy for chronic kidney disease.     

Aldosterone in renal disease

Blockade of the renin-angiotensin-aldosterone system has proved effective in retarding the progression of renal disease in the remnant kidney model, as well as other experimental diseases, and most importantly, in a range of progressive human renal diseases. Attention has focused on the role of angiotensin II in propagating progression both by its hemodynamic and non-hemodynamic actions. Recent evidence, predominantly in the remnant kidney model, indicates that the drugs used to block this hormone system, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, also lower aldosterone levels. Aldosterone as well as angiotensin II thus appears to be instrumental in sustaining the hypertension and fibroproliferative destruction of the residual kidney.     

Brain mineralocorticoid receptors: orchestrators of hypertension and end-organ disease

PURPOSE OF REVIEW: 'New' tasks have been discovered for aldosterone and its receptor, the mineralocorticoid receptor, within both epithelial tissues of vectorial ion and water transport, such as the kidney, and non-epithelial organs, including the brain, heart and vessels. Promising results of clinical trials using low doses of mineralocorticoid receptor antagonists to forestall end-organ disease is resulting in an increase in their use, yet the biology of the mineralocorticoid receptor is far from clear. RECENT FINDINGS: Mineralocorticoid receptors within the kidney, heart and blood vessels mediate direct effects of aldosterone, including tissue inflammation, hypertrophy and fibrosis, that are independent of blood pressure. Activation, by aldosterone, of mineralocorticoid receptors in the brain increases central sympathetic nervous system drive to the periphery, thereby producing hypertension through multiple mechanisms, and increases levels of proinflammatory cytokines in both the circulation and peripheral tissues. Blocking of the mineralocorticoid receptor of the forebrain lowers the levels of peripheral tissue cytokines, including those induced by ischemic injury in the heart. Aldosterone is produced within the heart, blood vessels and brain, potentially liberating regulation of local concentrations of the steroid from peripheral mechanisms of control. A conundrum yet to be explained is the ligand-dependent functional specificity of the mineralocorticoid receptor in some non-epithelial tissues, which may be crucial to our understanding the end-organ pathophysiology of hypertension. SUMMARY: New technology is rapidly adding layers of complexity to, rather than simplifying, our understanding of the facile terms 'hemodynamic homeostasis' and 'end-organ' disease, but within this new knowledge lies the promise of better, more precise treatment of hypertension and its sequelae.     

Long-term prevention of hypertension and end-organ damage in Ren-2 transgenic rats is achieved only with persistent but not transient AT1 receptor blockade

The aim of this study was first to evaluate the effects of persistent or transient blockade of the angiotensin II (ANG II) receptor AT(1) on the development of hypertension and end-organ damage in hypertensive Ren-2 transgenic rats (TGR), and second to assess the potential role of AT(2) receptors in the control of blood pressure (BP) in this monogenetic model of hypertension. Male heterozygous TGR and Hannover Sprague-Dawley (HanSD) rats fed a normal salt diet were treated from day 32 of age either persistently until the end of the experiment (day 100 of age) or transiently until day 56 of age with the selective AT(1) receptor antagonist candesartan or with the combination of candesartan and the AT(2) receptor antagonist PD 123319. Persistent treatment with candesartan completely prevented the rise in BP, proteinuria and the increase in left ventricular weight/body weight ratio, whereas transient treatment with candesartan was effective only as long as the drug was administered. In the presence of candesartan, PD 123319 was without effect. Our results show that in male heterozygous TGR persistent candesartan treatment completely prevented hypertension and end-organ damage as long as the drug was administered, whereas transient AT(1 )receptor blockade had no long-term effects.     

Effects of adjunct treatments on end-organ damage and histological injury severity in acute respiratory distress syndrome and multiorgan failure caused by smoke inhalation injury and burns

BackgroundWe investigated effects of mesenchymal stem cells (MSC) or low-flow extracorporeal life support (ECLS) as adjunctive treatments for acute respiratory distress syndrome (ARDS) due to inhalation injury and burns. We hypothesized that these interventions decrease histological end-organ damage.MethodsAnesthetized female swine underwent smoke inhalation injury and 40% TBSA burns, then critical care for 72 h. The following groups were studied: CTR (no injury, n = 4), ICTR (injured untreated, n = 10), Allo (injured treated with allogenic MSC, n = 10), Auto (injured treated with autologous MSC, n = 10), Hemo (injured and treated with the Hemolung low flow ECLS system, n = 9), and Nova (injured and treated with the NovaLung low flow ECLS system, n = 8). Histology scores from lung, kidneys, liver, and jejunum were calculated. Data are presented as means ± SEM.ResultsSurvival at 72 h was 100% in CTR; 40% in ICTR; 50% in Allo; 90% in Auto; 33% in Hemo; 63% in Nova. ARDS developed in 0/10 CTR; 10/10 ICTR; 8/9 Hemo; 5/8 Nova; 9/10 Allo; 6/10 Auto. Diffuse alveolar damage (DAD) was present in all injured groups. MSC groups had significantly lower DAD scores than ICTR animals (Allo 26.6 ± 3.4 and Auto 18.9 ± 1.5 vs. ICTR 46.8 ± 2.1, p < 0.001). MSC groups also had lower DAD scores than ECLS animals (Allo vs. Nova, p < 0.05, Allo vs. Hemo p < 0.001, Auto vs. Nova p < 0.001, Auto vs. Hemo, p < 0.001). Kidney injury ICTR (p < 0.05) and Hemo (p < 0.01) were higher than in CTR. By logistic regression, a PaO₂-to-FiO₂ ratio (PFR) < 300 was a function of the DAD score: logit (PFR < 300) = 0.84 + 0.072*DAD Score, odds ratio 1.074 (1.007, 1.147, p < 0.05) with a ROC AUC of 0.76, p < 0.001.ConclusionTreatment with Auto MSC followed by Allo and then Nova were most effective in mitigating ARDS and MOF severity in this model. Further studies will elucidate the role of combination therapies of MSC and ECLS as comprehensive treatments for ARDS and MOF.