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

ArticleinKidney International 69(11):2013-21 · July 2006with13 Reads
DOI: 10.1038/ · Source: PubMed
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.
    • "The novel finding of this study is that (1) subtotal nephrectomy induces an associated hypertension with an increased basal tone, an endothelial dysfunction, and an oxidative state and that (2) in vivo treatment with tempol improves arterial basal tone, NO levels, and oxidative stress without reversing hypertension, indicating that oxidative stress could be implicated in the vascular alterations, and that these disorders would occur early and independently to hypertension. It has been demonstrated that several models of renal mass reduction induce CKD and alter the renal function [6, 21, 22]. On the other hand, CKD is frequently associated with hypertension [23, 24]. "
    [Show abstract] [Hide abstract] ABSTRACT: Nonischemic 5/6 nephrectomized rat (NefR) is a model of chronic kidney disease. However, little is known about vascular dysfunction and its relation with hypertension in NefR. Aims. To evaluate possible alterations of endothelial function, NO-bioavailability, and basal tone in aorta from NefR and the role of oxidative stress. Sprague Dawley rats were divided into sham rats (SR), NefR, and NefR treated with tempol (NefR-T). Mean arterial pressure (MAP) and renal function were determined. In isolated aortic rings the following was measured: 1-endothelial function, 2-basal tone, 3-NO levels, 4-membrane potential (MP), and 5-oxidative stress. NefR increased MAP (SR: 119 ± 4 mmHg; n = 7; NefR: 169 ± 6; n = 8; P < 0.001). Tempol did not modify MAP (NefR-T: 168 ± 10; n = 6; P < 0.001). NefR showed endothelial dysfunction, increased basal tone and decreased NO levels (SR: 32 ± 2 nA; n = 7, NefR: 10 ± 2; n = 8; P < 0.001). In both in vitro and in vivo tempol improves basal tone, NO levels, and MP. Oxidative stress in NefR was reverted in NefR-T. We described, for the first time, that aorta from NefR presented increased basal tone related to endothelial dysfunction and decreased NO-bioavailability. The fact that tempol improves NO-contents and basal tone, without decrease MAP, indicates that oxidative stress could be implicated early and independently to hypertension, in the vascular alterations.
    Full-text · Article · Mar 2013
    • "Immature and distorted microvessels may present functional abnormalities, increased permeability or blind end- ings [65, 66] and new and fragile vessels might even exacerbate tissue injury [53]. These defects have not only been described in the kidney but also act systemically [67] . Simple administration of VEGF, therefore, is unlikely to be beneficial and in obstructive nephropathy, administration of VEGF actually worsened injury [68]. "
    [Show abstract] [Hide abstract] ABSTRACT: Tubulointerstitial hypoxia and peritubular capillary rarefaction are typical features of chronic progressive renal disease. In response to low oxygen supply, hypoxia-inducible factors (HIFs) are activated but until now, it is unclear if this increased expression leads to a stabilization of the disease process and thus is nephroprotective or contributes to interstitial fibrosis and/or tubular atrophy. This duality has also been described as far as vascular endothelial growth factor (VEGF), one of the major target genes of HIFs, is concerned. On the one hand, neoangiogenesis driven by VEGF, if intact, ameliorates hypoxia, on the other, VEGF is a potent pro-inflammatory mediator and neoangiogenesis, if defective because interference by other pathologies exaggerates injury. In summary, experimental data support the idea that dependent on timing and predominant pathology, hypoxia counter-regulatory factors exert beneficial or undesirable effects. Thus, before their therapeutic potential can be fully explored, a better way to characterize the clinical and pathophysiological situation in an individual patient is mandatory.
    Full-text · Article · Feb 2011
    • "The concentration of VEGF and PDGF in all groups was not significantly different (seeTable 1). In a study performed on subtotally nephrectomized rats, Jacobi et al. [28] indicated that CKD impairs ischemia-induced angiogenesis and reperfusion in model of hind-limb ischemia. They suspected that the increased concentration of nitric oxide inhibitor (ADMA) and decreased expression of VEGF and its receptors in skeletal muscles were associated with impaired angiogenesis. "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic kidney disease (CKD) is associated with muscle excess fatigue and diminished maximal whole body oxygen consumption, which in part could be depended on poor muscle microcirculatory network. The aim of this study was to assume the influence of different stages of CKD on microcirculation vessels in functionally different skeletal muscles--locomotor, the gastrocnemius muscle, and postural, the longissimus thoracis muscle. Male Wistar rats underwent sham operation (CON), uninephrectomy (CKD 1/2) and subtotal nephrectomy (CKD 5/6). Muscle samples were stained for an alkaline phosphatase to differentiate capillaries. The number of capillaries was estimated by a single observer in 10 microm transverse sections by point counting at a magnification of x 125 using an Image Analysis System Q 500 MC of Leica. Blood pressure and serum creatinine, haptoglobin, MCP-1, VEGF, and PDGF were measured. There were significant differences (p < 0.05) in CD (number of capillaries per 1 mm(2) of muscle tissue), C:F (capillary to fiber ratio), and CC/F (capillary contact per fiber). The CKD 1/2 group in gastrocnemius and longissimus muscle had 53% and 33% lower C:F; 56% and 33% lower CD; and 44% and 20% less CC/F than CON, respectively. The CKD 5/6 group in gastrocnemius and longissimus muscle had 46% and 20% lower C:F; 47% and 11% lower CD; and 48% and 25% less CC/F versus control, respectively. Blood pressure was higher in CKD 5/6 vs. CKD 1/2 and CON (145/95 vs. 107/87 and 119/77 mmHg, p < 0.05, respectively). CKD 5/6 had higher creatinine than CKD 1/2 and CON (1.22 vs. 0.83 and 0.74 mg/dL, p < 0.05, respectively). Haptoglobin was higher in CKD 1/2 and CKD 5/6 versus CON (1.68 and 1.63 vs. 0.70 mg/mL, p < 0.05, respectively). MCP-1 was higher in CKD 5/6 and CKD 1/2 versus CON (609 and 489 vs. 292 pg/mL, p < 0.05, respectively). There were no significant differences in serum growth factors concentration between groups. Capillary rarefaction is present in early stages of CKD. These changes are independent of blood pressure and progression of CKD. We suspected that muscle function has a big impact on microvasculature as capillaries rarefaction has been reduced more in locomotor than postural skeletal muscle.
    Full-text · Article · Feb 2008
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