PubMed Health⌕ Search

Biomedical subjects

Gerjan Navis

Publications and source records attributed to Gerjan Navis.

At least 19 recordsLinked to original sources
PubMed2007

Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II type 1 receptor (AT1R). In addition, bradykinin can induce the release of t-PA through a B2 receptor mechanism. In the present study, we aimed to investigate the epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels in a large population-based sample (n=2527). We demonstrated a strong significant interaction within genetic variations of the bradykinin B2 gene (P=0.002) and between ACE and bradykinin B2 (p=0.003) polymorphisms on t-PA levels in females. In males, polymorphisms in the bradykinin B2 and AT1R gene showed the most strong effect on t-PA levels (P=0.006). In both females and males, the bradykinin B2 gene interacted with AT1R gene on plasma PAI-1 levels (P=0.026 and P=0.039, respectively). In addition, the current study found a borderline significant interaction between PAI 4G5G and ACE I/D on plasma t-PA and PAI-1 levels. These results support the idea that the interplay between the renin-angiotensin, bradykinin, and fibrinolytic systems might play an important role in t-PA and PAI-1 biology.

Bradykinin↗
PubMed2006

Anaemia in chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well.

AIMS: Anaemia is prevalent in the chronic heart failure (CHF) population, but its cause is often unknown. The present study aims to investigate the relation between anaemia, renal perfusion, erythropoietin production, and fluid retention in CHF patients. METHODS AND RESULTS: We studied 97 patients with CHF, of which 15 had anaemia (Hb<13.0 g/dL in men and Hb<12.0 g/dL in women), without haematinic deficiencies. Glomerular filtration rate (GFR) and extracellular volume (ECV) were measured as the clearance and the distribution volume of constantly infused 125I-iothalamate, respectively. Effective renal plasma flow (ERPF) was determined as the clearance of 131I-hippuran. Anaemic CHF patients displayed significantly reduced GFR (P=0.002), ERPF (P=0.005) and EPO production (P=0.001), and an elevated ECV (P=0.015). Multivariable analysis demonstrated that lower GFR (P=0.003), lower ERPF (P=0.004), lower EPO production (P=0.006), and a higher ECV (P=0.001) were significant independent predictors of lower haemoglobin levels. CONCLUSION: Anaemia in CHF is not only independently associated with impaired renal perfusion and blunted EPO production, but to fluid retention as well.

Adolescent↗
PubMed2006

Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats.

Bone marrow-derived cells (BMDC) have been proposed to exert beneficial effects after renal ischemia/reperfusion injury (IRI) by engraftment in the tubular epithelium. However, BMDC can give rise to myofibroblasts and may contribute to fibrosis. BMDC contribution to the renal interstitial myofibroblast population in relation to fibrotic changes after IRI in rats was investigated. A model of unilateral renal IRI (45 min of ischemia) was used in F344 rats that were reconstituted with R26-human placental alkaline phosphatase transgenic BM to quantify BMDC contribution to the renal interstitial myofibroblast population over time. After IRI, transient increases in collagen III transcription and interstitial protein deposition were observed, peaking on days 7 and 28, respectively. Interstitial infiltrates of BMDC and myofibroblasts reached a maximum on day 7 and gradually decreased afterward. Over time, an average of 32% of all interstitial alpha-smooth muscle actin-positive myofibroblasts coexpressed R26-human placental alkaline phosphatase and, therefore, were derived from the BM. BMD myofibroblasts produced procollagen I protein and therefore were functional. The postischemic kidney environment was profibrotic, as demonstrated by increased transcription of TGF-beta and decreased transcription of bone morphogenic protein-7. TGF-beta protein was present predominantly in interstitial myofibroblasts but not in BMD myofibroblasts. In conclusion, functional BMD myofibroblasts infiltrate in the postischemic renal interstitium and are involved in extracellular matrix production.

Animals↗
PubMed2006

Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunction.

BACKGROUND: Renal function is an important risk marker for morbidity and mortality in chronic heart failure (CHF) and is often estimated with the use of creatinine-based formulas. However, these formulas have never been validated in a wide range of CHF patients. We validated 3 commonly used formulas estimating glomerular filtration rate (GFR) with true GFR in CHF patients. Furthermore, we compared the prognostic value of these formulas for cardiovascular outcome with that of true GFR during 12 months of follow-up. METHODS AND RESULTS: In 110 CHF patients (age, 57+/-11.7 years; left ventricular ejection fraction, 0.27+/-0.09; NYHA class, 2.5+/-0.9), we measured 125I-iothalamate clearance. Cockcroft-Gault (GFR(cg)), Modification of Diet in Renal Disease (MDRD), and simplified MDRD (sMDRD) equations were used as creatinine-based renal function estimations. Furthermore, 24-hour creatinine clearance (CrCl) was determined. CrCl and GFR(cg) were the most accurate. MDRD was most precise formula, although it was also highly biased. All formulas overestimated in the lower ranges and underestimated in the upper ranges of the GFR corrected for body surface area. The predictive performance of the formulas was best in severe CHF (NYHA classes III and IV). The prognostic value of CrCl and MDRD for cardiovascular outcome was comparable to that of GFR, the sMDRD was slightly less, and the GFR(cg) had a significantly worse prognostic value. CONCLUSIONS: In the more severe ranges of CHF, creatinine-based formulas and CrCl corrected for body surface area appeared to be more precise and accurate in estimating true GFR corrected for body surface area. The MDRD formula is the most precise and has a good prognostic value, whereas the sMDRD is slightly less accurate but uses fewer parameters, which makes this formula a practical alternative in clinical practice.

Aged↗
PubMed2006

Induction of glomerular heparanase expression in rats with adriamycin nephropathy is regulated by reactive oxygen species and the renin-angiotensin system.

Heparan sulfate (HS) in the glomerular basement membrane (GBM) is important for regulation of the charge-dependent permeability. Heparanase has been implicated in HS degradation in several proteinuric diseases. This study analyzed the role of heparanase in HS degradation in Adriamycin nephropathy (AN), a model of chronic proteinuria-induced renal damage. Expression of heparanase, HS, and the core protein of agrin (to which HS is attached) was determined on kidney sections from rats with AN in different experiments. First, expression was examined in a model of unilateral AN in a time-course study at 6-wk intervals until week 30. Second, rats were treated with the hydroxyl radical scavenger dimethylthiourea (DMTU) during bilateral AN induction. Finally, 6 wk after AN induction, rats were treated with angiotensin II receptor type 1 antagonist (AT1A) or vehicle for 2 wk. Heparanase expression was increased in glomeruli of rats with AN, which correlated with HS reduction at all time points and in all experiments. Treatment with DMTU prevented the increased heparanase expression, the loss of GBM HS, and reduced albuminuria. Finally, treatment of established proteinuria with AT1A significantly reduced heparanase expression and restored glomerular HS. In conclusion, an association between heparanase expression and reduction of glomerular HS in AN was observed. The effects of DMTU suggest a role for reactive oxygen species in upregulation of heparanase. Antiproteinuric treatment by AT1A decreased heparanase expression and restored HS expression. These results suggest involvement of radicals and angiotensin II in the modulation of GBM permeability through HS and heparanase expression.

Agrin↗
PubMed2006

Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase.

Kidney injury molecule-1 (Kim-1) is associated with ischemic and proteinuric tubular injury; however, whether dysregulation of the renin-angiotensin system (RAS) can also induce Kim-1 is unknown. We studied Kim-1 expression in homozygous Ren2 rats, characterized by renal damage through excessive RAS activation. We also investigated whether antifibrotic treatment (RAS blockade or p38 MAP kinase inhibition) would affect Kim-1 expression. At 7 wk of age, homozygous Ren2 rats received a nonhypotensive dose of candesartan (0.05 mg x kg(-1) x day(-1) sc) or the p38 inhibitor SB-239063 (15 mg x kg(-1) x day(-1) sc) for 4 wk; untreated Ren2 and Sprague-Dawley (SD) rats served as controls. Kim-1 mRNA and protein expression were determined by quantitative PCR and immunohistochemistry, respectively, and related to markers of prefibrotic renal damage. Urinary Kim-1 was measured in 8-wk-old Ren2 and SD rats with and without angiotensin-converting enzyme inhibition (ramipril, 1 mg x kg(-1) x day(-1) in drinking water for 4 wk). Untreated Ren2 rats showed a >20-fold increase in renal Kim-1 mRNA (expressed as Kim-1-to-GAPDH ratio): 75.5 +/- 43.6 vs. 3.1 +/- 1.0 in SD rats (P < 0.01). Candesartan and SB-239063 strongly reduced Kim-1 mRNA: 3.1 +/- 1.5 (P < 0.01) and 9.8 +/- 4.2 (P < 0.05), respectively. Kim-1 protein expression in damaged tubules paralleled mRNA expression. Kim-1 expression correlated with renal osteopontin, alpha-smooth muscle actin, and collagen III expression and with tubulointerstitial fibrosis. Damaged tubular segments expressing activated p38 also expressed Kim-1. Urinary Kim-1 was increased in Ren2 vs. SD (458 +/- 70 vs. 27 +/- 2 pg/ml, P < 0.01) rats and abolished in Ren2 rats treated with ramipril (33 +/- 5 pg/ml, P < 0.01). Kim-1 is associated with development of RAS-mediated renal damage. Antifibrotic treatment through RAS blockade or p38 MAP kinase inhibition reduced Kim-1 in the homozygous Ren2 model.

Aldosterone↗
PubMed2006

Incidental renal artery stenosis is an independent predictor of mortality in patients with peripheral vascular disease.

In patients with peripheral vascular disease (PVD), mortality is high and renal artery stenosis (RAS) is a frequent incidental finding. RAS carries a high risk for mortality, but whether incidentally discovered RAS is a risk factor for mortality is unknown. The prognostic impact of incidental RAS for mortality was studied in 550 consecutive patients who underwent intra-arterial digital subtraction angiography for PVD in a single center between 1997 and 2000. In 491 patients (336 men, 155 women; mean follow-up 3.8 +/- 1.9 yr), the renal arteries were visualized and follow-up data were available. RAS (diameter reduction > 50%) was present in 26% of the patients. Mortality in the RAS group was 59 versus 28% in the non-RAS group (odds ratio 3.8; 95% confidence interval 2.5 to 5.7; P < 0.0001). Diabetes, previous myocardial infarction, history of PVD, stroke, and hypertension were more frequent in the RAS group; age was higher and GFR was lower in the RAS group. Therefore, RAS was associated with elevated mortality and increased prevalence of cardiovascular risk factors. Cox regression analysis showed that RAS was an independent predictor for mortality (P = 0.005), along with age, diabetes, smoking, previous myocardial infarction, history of PVD, and stroke. In patients who were evaluated for PVD by digital subtraction angiography, mortality was high. Incidental RAS was a frequent finding and an independent predictor for mortality. Whether RAS is a marker for or, alternatively, a mediator of the poor prognosis and whether prognosis can be improved by specific intervention should be the subject of future prospective studies.

Aged↗
PubMed2006

A role for CETP TaqIB polymorphism in determining susceptibility to atrial fibrillation: a nested case control study.

BACKGROUND: Studies investigating the genetic and environmental characteristics of atrial fibrillation (AF) may provide new insights in the complex development of AF. We aimed to investigate the association between several environmental factors and loci of candidate genes, which might be related to the presence of AF. METHODS: A nested case-control study within the PREVEND cohort was conducted. Standard 12 lead electrocardiograms were recorded and AF was defined according to Minnesota codes. For every case, an age and gender matched control was selected from the same population (n = 194). In addition to logistic regression analyses, the multifactor-dimensionality reduction (MDR) method and interaction entropy graphs were used for the evaluation of gene-gene and gene-environment interactions. Polymorphisms in genes from the Renin-angiotensin, Bradykinin and CETP systems were included. RESULTS: Subjects with AF had a higher prevalence of electrocardiographic left ventricular hypertrophy, ischemic heart disease, hypertension, renal dysfunction, elevated levels of C-reactive protein (CRP) and increased urinary albumin excretion as compared to controls. The polymorphisms of the Renin-angiotensin system and Bradykinin gene did not show a significant association with AF (p > 0.05). The TaqIB polymorphism of the CETP gene was significantly associated with the presence of AF (p < 0.05). Using the MDR method, the best genotype-phenotype models included the combination of micro- or macroalbuminuria and CETP TaqIB polymorphism, CRP >3 mg/L and CETP TaqIB polymorphism, renal dysfunction and the CETP TaqIB polymorphism, and ischemic heart disease and CETP TaqIB polymorphism (1000 fold permutation testing, P < 0.05). Interaction entropy graph showed that the combination of albuminuria and CETP TaqIB polymorphism removed the most entropy. CONCLUSION: CETP TaqIB polymorphism is significantly associated with the presence of AF in the context of micro- or macroalbuminuria, elevated C-reactive protein, renal dysfunction, and ischemic heart disease.

Atrial Fibrillation↗
PubMed2006

Difference in long-term prognostic value of renal function between ischemic and non-ischemic mild heart failure.

INTRODUCTION: Renal function is one of the strongest prognostic markers in patients with chronic heart failure, but it has been suggested that this might be due to (local, i.e. renal) vascular atherosclerosis. The aim of the present study is to evaluate the prognostic value of renal function in both ischemic and non-ischemic mild chronic heart failure. METHODS: From 161 patients with early chronic heart failure and NYHA class II, who had been enrolled in a multicenter trial, ischemic chronic heart failure was present in 120 patients and non-ischemic chronic heart failure in 41 patients. Estimated glomerular filtration rate was calculated by the Cockcroft-Gault equation (GFRc). RESULTS: Follow-up duration was 13 years (mean 11.7 years). Mean age was 60.5+/-8.0 years, 86% was male and mean left ventricular ejection fraction was 0.29+/-0.08. Baseline characteristics were not statistically different between the groups. Multivariate Cox regression analysis revealed that in non-ischemic chronic heart failure, renal function was an important predictor of all-cause mortality (Relative Risk; 1.65 (1.05-2.58); p=0.029). In contrast, in ischemic chronic heart failure, renal function was not related to all-cause mortality (Relative Risk; 1.07 (0.92-1.23); p=0.40). CONCLUSION: In mild chronic heart failure, renal function is a prognostic risk marker for long-term mortality in non-ischemic chronic heart failure, but not in patients with coronary artery disease. These data suggest that renal vascular abnormalities are not primarily responsible for the prognostic value of renal function in patients with mild chronic heart failure.

Aged↗
PubMed2006

The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-1 levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-1 (P < 0.01) compared to females. When stratifying females by menopausal status, PAI-1 levels were only significantly different between pre-menopausal females and males (p < 0.001). Furthermore, we found that age, body mass index, and waist-to-hip ratio were significant predictors of t-PA and PAI-1 in both females and males, and that the regression relationships between these factors and plasma t-PA and PAI-1 were dependent on gender. In addition, we found that the PAI-1 4G/5G polymorphism was a significant predictor of PAI-1 levels in both females and males, that the angiotensin II type I receptor A1166C was a significant predictor of t-PA and PAI-1 levels in females, and that the bradykinin receptor B2 58CT polymorphism was a significant predictor of t-PA levels in females. In conclusion, this large population-based study showed that t-PA and PAI-1 levels are determined by several demographic and genetic factors involved in the fibrinolytic, RAS and bradykinin system. In addition, the results support the idea that the biology of t-PA and PAI-1 is different between females and males.

Adult↗
PubMed2005

Vascular function and mild renal impairment in stable coronary artery disease.

OBJECTIVE: In patients with coronary artery disease, the concomitant presence of renal function impairment is associated with decreased survival. We aimed to assess whether in coronary artery diseased patients renal function impairment is associated with systemic vascular function, functional parameters of the renin-angiotensin system, or inflammation as potential mediators for cardiovascular risk. METHODS AND RESULTS: We studied 125 patients, 87% male, with a mean age of 62.2+/-8.2 years; 72% had 3-vessel disease, and mean renal function was 74+/-13 mL/min per 1.73 m2. Internal thoracic artery rings were sampled during coronary bypass surgery and used for in vitro vascular measurements. We could not establish an association between endothelium-dependent vasorelaxation (response to methacholine) and renal function. In addition, vascular response to potassium chloride, phenylephrine, and angiotensin II were not associated with renal function. Finally, serum angiotensin-converting enzyme (ACE) activity, usage of ACE inhibitors, C-reactive protein, and soluble intercellular adhesion molecule 1 were not related to renal function. CONCLUSIONS: In coronary artery disease patients, mild renal function impairment is not associated with systemic vasomotor responsiveness, inflammation, or functional systemic parameters of the renin-angiotensin system. The relation between systemic endothelial dysfunction and mild renal insufficiency might be more complicated than previously thought.

Aged↗
PubMed2005

Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients.

Tissue advanced glycation end products (AGE) are a measure of cumulative metabolic stress and trigger cytokines driven inflammatory reactions. AGE are thought to contribute to the chronic complications of diabetes and ESRD. Tissue autofluorescence is related to the accumulation of AGE. Therefore, skin autofluorescence (AF) may provide prognostic information on mortality in hemodialysis (HD) patients. Skin AF was measured noninvasively with an AF reader at baseline in 109 HD patients. Overall and cardiovascular mortality was monitored prospectively during a period of 3 yr. The AF reader was validated against AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the 109 (38.5%) HD patients died. Cox regression analysis showed that AF was an independent predictor of overall and cardiovascular mortality (for overall mortality odds ratio [OR] 3.9), as were pre-existing cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the variance in AF could be attributed to the independent effects of age, dialysis and renal failure duration, presence of diabetes, triglycerides levels, and C-reactive protein. AF was also independently linked to the presence of CVD at baseline (OR 8.8; P < 0.001). AF correlated with collagen-linked fluorescence (r = 0.71, P < 0.001), pentosidine (r = 0.75, P < 0.001), and carboxy(m)ethyllysine (both r = 0.45, P < 0.01). Skin AF is a strong and independent predictor of mortality in ESRD. This supports a role for AGE as a contributor to mortality and CVD and warrants interventions specifically aimed at AGE accumulation.

Adult↗
PubMed2005

Cellular cholesterol efflux to plasma from proteinuric patients is elevated and remains unaffected by antiproteinuric treatment.

BACKGROUND: Lipid derangements are assumed to contribute to the elevated cardiovascular risk in proteinuric patients. The impact of proteinuria on reverse cholesterol transport (RCT) is unknown. The first step in RCT, cellular cholesterol efflux to plasma, may be altered in proteinuria, consequent to changes in pre-beta high-density lipoprotein (HDL) formation and plasma phospholipid transfer protein (PLTP) activity. METHODS: In six non-diabetic male patients with nephrotic-range proteinuria and 12 matched healthy men, plasma (apo)lipoproteins, pre-beta HDL formation, PLTP activity as well as the ability of plasma to promote cholesterol efflux out of cultured human skin fibroblasts were determined. These variables were also measured in response to antiproteinuric treatment, consisting of single and dual RAAS blockade by losartan and lisinopril. RESULTS: Plasma total cholesterol (P<0.05), triglycerides (P<0.05), apolipoprotein (apo) A-I (P<0.001), apo B (P<0.001), PLTP activity (P<0.005) and pre-beta HDL formation (P<0.001) were higher in proteinuric patients. Cellular cholesterol efflux to plasma from proteinuric patients was 41% higher than to plasma from healthy subjects (P<0.001). Reduction of proteinuria from 5.0 to 1.4 g/day by dual RAAS blockade was associated with a 23% reduction in plasma apo B levels (P<0.05). Pre-beta HDL formation and plasma PLTP activity did not change significantly. Combined antiproteinuric treatment did not reduce the elevated cellular cholesterol efflux. CONCLUSION: Cellular cholesterol efflux to plasma from patients with nephrotic-range proteinuria is enhanced, in conjunction with elevated pre-beta HDL formation and plasma PLTP activity. These changes may attenuate the cardiovascular risk associated with proteinuria-associated hyperlipidaemia. Antiproteinuric therapy lowers plasma apo B, but does not affect cell-derived cholesterol efflux, suggesting that this therapy beneficially affects cardiovascular risk in proteinuric patients.

Adult↗
PubMed2005

Renal accumulation of pentosidine in non-diabetic proteinuria-induced renal damage in rats.

BACKGROUND: Advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic glomerulopathy. The role of AGEs in non-diabetic renal damage is not well characterized. First, we studied whether renal AGE accumulation occurs in non-diabetic proteinuria-induced renal damage and whether this is ameliorated by renoprotective treatment. Secondly, we investigated whether renal AGE accumulation was due to intrarenal effects of local protein trafficking. METHODS: Pentosidine was measured (by high-performance liquid chromatography) in rats with chronic bilateral adriamycin nephropathy (AN), untreated and treated with lisinopril. Age-matched healthy rats served as negative controls. Secondly, we compared renal pentosidine in mild proteinuric and non-proteinuric kidneys of unilateral AN and in age-matched controls at 12 and 30 weeks. Intrarenal localization of pentosidine was studied by immunohistochemistry. RESULTS: Renal pentosidine was elevated in untreated AN (0.14+/-0.04 micromol/mol valine) vs healthy controls (0.04+/-0.01 micromol/mol valine, P<0.01). In lisinopril-treated AN, pentosidine was lower (0.09+/-0.02 micromol/mol valine) than in untreated AN (P<0.05). In unilateral proteinuria, pentosidine was similar in non-proteinuric and proteinuric kidneys. After 30 weeks of unilateral proteinuria, pentosidine was increased in both kidneys (0.26+/-0.10 micromol/mol valine) compared with controls (0.18+/-0.06 micromol/mol valine, P<0.05). Pentosidine (AN, week 30) was also increased compared with AN at week 12 (0.16+/-0.06 micromol/mol valine, P<0.01). In control and diseased kidneys, pentosidine was present in the collecting ducts. In proteinuric kidneys, in addition, pentosidine was present in the brush border and cytoplasm of dilated tubular structures, i.e. at sites of proteinuria-induced tubular damage. CONCLUSION: Pentosidine accumulates in non-diabetic proteinuric kidneys in damaged tubules, and renoprotective treatment by angiotensin-converting enzyme (ACE) inhibitors inhibits AGE accumulation, supporting a relationship between abnormal renal protein trafficking, proteinuria-induced tubular damage and tubular pentosidine accumulation. Future studies, applying specific AGE inhibitors, should be conducted to provide insight into the pathophysiological significance of renal AGEs in non-diabetic renal disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Reduced cyclooxygenase involvement in vascular endothelial function in rat renal transplantation.

BACKGROUND: Cardiovascular disease is a major cause of death following renal transplantation. Mechanisms leading to vascular dysfunction outside the transplanted organ involve common risk factors such as hypertension, hypercholesterolemia, proteinuria, but immune-mediated factors may also be involved. We hypothesized that transplantation-associated risk factors are involved in the development of vascular dysfunction following renal transplantation. METHODS: Vascular function was studied in Fisher to Lewis allografts. Lewis to Lewis syngrafted rats served as controls. All rats received cyclosporin A for 10 days. Allografts were treated with ACE inhibition or AT1 receptor blockade or left untreated. After 34 weeks, aorta rings were studied for contractile and dilator responses in the presence or absence of L-NMMA and/or indomethacin. Tissue sections were immunostained for COX-1 and COX-2. RESULTS: In contrast to syngrafts and treated allografts, untreated allografts developed proteinuria and hypercholesterolemia. In aortic rings, NOS inhibition similarly increased contractile responses and decreased dilator responses in syngrafts and allografts, indicating comparable NO pathways. In contrast, indomethacin affected contractile and dilator responses in syngrafts, but not in treated and untreated allografts, indicating absence of COX-derived prostanoids in control over vascular tone in allografts. This was in line with immunohistologic analysis demonstrating reduced aortic COX-2 expression in allografts. COX-1 expression was unaltered. Interestingly, RAS blockade quantitatively increased endothelium-dependent dilation without qualitatively altering COX function and expression. CONCLUSION: Involvement of COX-derived prostaglandins in vascular endothelial function outside the transplanted organ is strongly diminished after allogeneic renal transplantation. RAS blockade improves common cardiovascular risk factors and endothelium-dependent dilation, but fails to restore prostaglandin function.

Animals↗