Subtotal nephrectomy impairs ischemia-induced angiogenesis and hindlimb re-perfusion in rats.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Kidney International (Impact Factor: 8.52). 07/2006; 69(11):2013-21. DOI: 10.1038/
Source: PubMed

ABSTRACT Kidney disease is associated with increased cardiovascular morbidity, but underlying mechanisms are poorly understood. We tested the hypothesis that chronic renal insufficiency impairs angioadaptation in a rat model of hindlimb ischemia. Twenty male Sprague-Dawley rats (8 weeks old) underwent subtotal nephrectomy (5/6SNX) or sham surgery (each n=10). Ten weeks later, unilateral hindlimb ischemia was induced in all animals. Hindlimb perfusion was assessed by laser Doppler perfusion imaging and fluorescent microsphere injection studies 2 weeks after surgery. Ischemia-induced angiogenesis was measured by analyzing capillary density using CD31 immunofluorescence. Expression of vascular endothelial growth factor (VEGF), its receptors (VEGFRs) and inducible as well as endothelial nitric oxide (NO) synthase was measured by real-time reverse transcription-polymerase chain reaction. Laser Doppler hindpaw perfusion was significantly reduced in 5/6SNX compared to sham-operated animals. Impaired hindlimb re-perfusion in 5/6SNX vs control rats was confirmed by fluorescent microsphere injection studies (relative perfusion of ischemic vs non-ischemic limb: 68.9+/-6.4 vs 92.4+/-3.6%, P=0.005). Ischemic skeletal muscle neovascularization increased to a greater extent in sham-operated compared to 5/6SNX rats (69+/-8 vs 29+/-7%, P<0.05). VEGF and VEGFR-1/2 mRNA expression increased in ischemic hindlimbs of control rats, whereas no change or a decrease was observed in 5/6SNX. In contrast, inducible and endothelial NO synthase expression did not significantly differ between sham and 5/6SNX rats. Chronic renal insufficiency impairs angiogenesis and limb perfusion in a rat hindlimb ischemia model. Impaired angioadaptation may contribute to the poor prognosis of patients with renal failure suffering from peripheral arterial disease.

  • [Show abstract] [Hide abstract]
    ABSTRACT: We sought to determine the association of major cardiovascular risk factors and other comorbidities with the presence or absence of coronary collateral (CC) circulation. All electronic medical records from 2010 to 2011 were retrospectively reviewed. A total of 563 patients were divided into 2 groups: CC present (180) and CC absent (383). Smoking (P = .012, odds ratio [OR] 1.58), hypercholesterolemia (P = .001, OR 2.21), and hypertension (P = .034, OR 1.75) were associated with the presence of CC. Increasing body mass index (BMI, P = .001) and decreasing estimated glomerular filtration rate (eGFR, P = .042) were associated with the absence of CC. On multivariable linear regression analysis, hypercholesterolemia (P = .001, OR 2.28), BMI (P = .012, OR 0.77), and eGFR (P = .001, OR 0.70) were found to be independently associated with CC. Our findings will help predict patient populations more likely to have presence or absence of CC circulation.
    Angiology 08/2014; DOI:10.1177/0003319714545342 · 2.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose of review Left ventricular hypertrophy (LVH) is common in end-stage renal disease (ESRD) and has been advocated as a therapeutic target. We review the considerations for targeting LVH as a modifiable risk factor in ESRD. Recent findings Pathologic myocardial changes underlying LVH provide an ideal substrate for the spread of arrhythmia and may be key contributors to the occurrence of sudden death in ESRD. LVH is present in 68-89% of incident hemodialysis patients and is frequently progressive, although regression is observed in a minority of patients. Higher degrees of baseline LVH, as well as greater increases in left ventricular mass index over time, are associated with decreased survival, but whether these associations are causal remains uncertain. Several interventions, including angiotensin blockade and frequent dialysis, can reduce the left ventricular mass index, but whether this is associated with improved survival has not been definitively demonstrated. Summary LVH is a highly prevalent and reversible risk factor, which holds promise as a novel therapeutic target in ESRD. Interventional trials are needed to provide additional evidence that LVH regression improves survival before prevention and reversal of LVH can be definitively adopted as a therapeutic paradigm in ESRD.
    Current Opinion in Nephrology and Hypertension 11/2014; 23(6):578-585. DOI:10.1097/MNH.0000000000000067 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Sudden cardiovascular death is increased in chronic kidney disease (CKD). Experimental CKD models suggest that angiogenesis and nitric oxide (NO) inhibitors induce myocardial fibrosis and microvascular dropout thereby facilitating arrhythmogenesis. We undertook this study to characterize associations of CKD with human myocardial pathology, NO-related circulating angiogenesis inhibitors, and endothelial cell behavior. Methods: We compared heart (n = 54) and serum (n = 162) samples from individuals with and without CKD, and assessed effects of serum on human coronary artery endothelial cells (HCAECs) in vitro. Left ventricular fibrosis and capillary density were quantified in post-mortem samples. Endothelial to mesenchymal transition (EndMT) was assessed by immunostaining of post-mortem samples and RNA expression in heart tissue obtained during cardiac surgery. Circulating asymmetric dimethylarginine (ADMA), endostatin (END), angiopoietin-2 (ANG), and thrombospondin-2 (TSP) were measured, and the effect of these factors and of subject serum on proliferation, apoptosis, and EndMT of HCAEC was analyzed. Results: Cardiac fibrosis increased 12% and 77% in stage 3-4 CKD and ESRD and microvascular density decreased 12% and 16% vs. preserved renal function. EndMT-derived fibroblast proportion was 17% higher in stage 3-4 CKD and ESRD (P-trend = 0.02). ADMA, ANG, TSP, and END concentrations increased in CKD. Both individual factors and CKD serum increased HCAEC apoptosis (P = 0.02), decreased proliferation (P = 0.03), and induced EndMT. Conclusions: CKD is associated with an increase in circulating angiogenesis and NO inhibitors, which impact proliferation and apoptosis of cardiac endothelial cells and promote EndMT, leading to cardiac fibrosis and capillary rarefaction. These processes may play key roles in CKD-associated CV disease.
    International Journal of Cardiology 07/2014; 176(1). DOI:10.1016/j.ijcard.2014.06.062 · 6.18 Impact Factor


Available from

Barbara Namer