Blunted transcriptional response to skeletal muscle ischemia in rats with chronic kidney disease: potential role for impaired ischemia-induced angiogenesis

Heiß, Rafael; Fahlbusch, Fabian; Jacobi, Johannes; Daniel, Christoph; Ekici, Arif B.; Cordasic, Nada; Amann, Kerstin; Hartner, Andrea; Hilgers, Karl F.

doi:10.1152/physiolgenomics.00124.2016

Cited by 6 publications

(3 citation statements)

References 38 publications

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“…Specifically, it was shown that nephrectomized rats subjected to femoral artery ligation displayed decreased limb perfusion recovery, lower muscle capillary density, and lower expression of VEGF and VEGFR-1 in ischemic muscles 93 . Another study in rats reported that CKD resulted in decreased expression of multiple genes involved in angiogenesis and vascular growth 94 . Interestingly, we observed normal perfusion recovery in the paw and tibialis anterior muscles of CKD mice, as well as normal capillary density.…”

Section: Discussionmentioning

confidence: 99%

Chronic kidney disease exacerbates ischemic limb myopathy in mice via altered mitochondrial energetics

Berru¹,

Gray²,

Thome³

et al. 2019

Sci Rep

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Chronic kidney disease (CKD) substantially increases the severity of peripheral arterial disease (PAD) symptomology, however, the biological mechanisms remain unclear. The objective herein was to determine the impact of CKD on PAD pathology in mice. C57BL6/J mice were subjected to a diet-induced model of CKD by delivery of adenine for six weeks. CKD was confirmed by measurements of glomerular filtration rate, blood urea nitrogen, and kidney histopathology. Mice with CKD displayed lower muscle force production and greater ischemic lesions in the tibialis anterior muscle (78.1 ± 14.5% vs. 2.5 ± 0.5% in control mice, P < 0.0001, N = 5–10/group) and decreased myofiber size (1661 ± 134 μm2 vs. 2221 ± 100 μm2 in control mice, P < 0.01, N = 5–10/group). This skeletal myopathy occurred despite normal capillary density (516 ± 59 vs. 466 ± 45 capillaries/20x field of view) and limb perfusion. CKD mice displayed a ~50–65% reduction in muscle mitochondrial respiratory capacity in ischemic muscle, whereas control mice had normal mitochondrial function. Hydrogen peroxide emission was modestly higher in the ischemic muscle of CKD mice, which coincided with decreased oxidant buffering. Exposure of cultured myotubes to CKD serum resulted in myotube atrophy and elevated oxidative stress, which were attenuated by mitochondrial-targeted therapies. Taken together, these findings suggest that mitochondrial impairments caused by CKD contribute to the exacerbation of ischemic pathology.

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Section: Discussionmentioning

confidence: 99%

Chronic kidney disease exacerbates ischemic limb myopathy in mice via altered mitochondrial energetics

Berru¹,

Gray²,

Thome³

et al. 2019

Sci Rep

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show abstract

“…Angiogenesis is severely impaired in all forms of experimental renal failure, including acute kidney injury (AKI), chronic (CKD) or progressive (AKI-to-CKD transition) disease [19]. The physiological response to hypoxia is mainly driven by hypoxia-induced factors such as HIF-1α and a network of target genes in a coordinated fashion [20]. However, there is evidence for paradoxical down-regulation of HIF-1α and its target genes in murine models of CKD [18,21] and in a rat model of hindlimb ischemia [22,23].…”

Section: Skeletal Muscle After Hindlimb Ischemiamentioning

confidence: 99%

Microvascular disease in chronic kidney disease: the base of the iceberg in cardiovascular comorbidity

2020

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Chronic kidney disease (CKD) is a relentlessly progressive disease with a very high mortality mainly due to cardiovascular complications. Endothelial dysfunction is well documented in CKD and permanent loss of endothelial homeostasis leads to progressive organ damage. Most of the vast endothelial surface area is part of the microcirculation, but most research in CKD-related cardiovascular disease (CVD) has been devoted to macrovascular complications. We have reviewed all publications evaluating structure and function of the microcirculation in humans with CKD and animals with experimental CKD. Microvascular rarefaction, defined as a loss of perfused microvessels resulting in a significant decrease in microvascular density, is a quintessential finding in these studies. The median microvascular density was reduced by 29% in skeletal muscle and 24% in the heart in animal models of CKD and by 32% in human biopsy, autopsy and imaging studies. CKD induces rarefaction due to the loss of coherent vessel systems distal to the level of smaller arterioles, generating a typical heterogeneous pattern with avascular patches, resulting in a dysfunctional endothelium with diminished perfusion, shunting and tissue hypoxia. Endothelial cell apoptosis, hypertension, multiple metabolic, endocrine and immune disturbances of the uremic milieu and specifically, a dysregulated angiogenesis, all contribute to the multifactorial pathogenesis. By setting the stage for the development of tissue fibrosis and end organ failure, microvascular rarefaction is a principal pathogenic factor in the development of severe organ dysfunction in CKD patients, especially CVD, cerebrovascular dysfunction, muscular atrophy, cachexia, and progression of kidney disease. Treatment strategies for microvascular disease are urgently needed.

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“…As reported previously, quality of isolated RNA samples was determined using the Agilent 2100 Bioanalyzer equipped with an Agilent RNA 6000 Nano kit and related software (Agilent, Santa Clara, CA) [ 43 ]. RNA integrity number (RIN) values of ≥ 5 were deemed suitable for analysis [ 44 ].…”

Section: Methodsmentioning

confidence: 99%

RNA sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension

et al. 2021

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In malignant hypertension, far more severe kidney injury occurs than in the “benign” form of the disease. The role of high blood pressure and the renin–angiotensin–aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p < 0.05). Eight hundred eighty-six genes were exclusively regulated in MH only. Principal component analysis revealed a separated clustering of the three groups. The data pointed to an upregulation of many inflammatory mechanisms in MH including pathways which previously attracted relatively little attention in the setting of hypertensive kidney injury: Transcripts from all three complement activation pathways were upregulated in MH compared to NMH but not in NMH compared with controls; immunohistochemistry confirmed complement deposition in MH exclusively. The expression of chemokines attracting neutrophil granulocytes (CXCL6) and infiltration of myeloperoxidase-positive cells were increased only in MH rats. The data suggest that these pathways, especially complement deposition, may contribute to kidney injury under MH. Key messages The most severe hypertension-induced kidney injury occurs in malignant hypertension. In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades. Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.

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Blunted transcriptional response to skeletal muscle ischemia in rats with chronic kidney disease: potential role for impaired ischemia-induced angiogenesis

Cited by 6 publications

References 38 publications

Chronic kidney disease exacerbates ischemic limb myopathy in mice via altered mitochondrial energetics

Chronic kidney disease exacerbates ischemic limb myopathy in mice via altered mitochondrial energetics

Microvascular disease in chronic kidney disease: the base of the iceberg in cardiovascular comorbidity

RNA sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension

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