Osteopontin deficiency dampens the pro-atherogenic effect of uraemia

Pedersen, T.; Madsen, Marie; Junker, Nanna; Christoffersen, Christina; Vikeså, Jonas; Bro, Susanne; Hultgårdh‐Nilsson, Anna; Nielsen, Lars Bo

doi:10.1093/cvr/cvt049

Cited by 17 publications

(14 citation statements)

References 46 publications

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“…Similarly, a recent study by Ghosh et al also did not detect increased fibrosis in this model [24]. Furthermore, previous studies in our group [8, 25, 26] have established that kidney function after 5/6 NX does not deteriorate progressively with time (up to 1 year) in C57Bl6/J mice. It is therefore possible that 5/6 NX on a C57Bl6/J background merely reflect early stages of kidney injury, incl.…”

Section: Discussionsupporting

confidence: 83%

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Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

et al. 2016

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Chronic kidney disease (CKD) leads to uremia. CKD is characterized by a gradual increase in kidney fibrosis and loss of kidney function, which is associated with a progressive increase in risk of atherosclerosis and cardiovascular death. To prevent progression of both kidney fibrosis and atherosclerosis in uremic settings, insight into new treatment options with effects on both parameters is warranted. The GLP-1 analogue liraglutide improves glucose homeostasis, and is approved for treatment of type 2 diabetes. Animal studies suggest that GLP-1 also dampens inflammation and atherosclerosis. Our aim was to examine effects of liraglutide on kidney fibrosis and atherosclerosis in a mouse model of moderate uremia (5/6 nephrectomy (NX)). Uremic (n = 29) and sham-operated (n = 14) atherosclerosis-prone low density lipoprotein receptor knockout mice were treated with liraglutide (1000 μg/kg, s.c. once daily) or vehicle for 13 weeks. As expected, uremia increased aortic atherosclerosis. In the remnant kidneys from NX mice, flow cytometry revealed an increase in the number of monocyte-like cells (CD68+F4/80-), CD4+, and CD8+ T-cells, suggesting that moderate uremia induced kidney inflammation. Furthermore, markers of fibrosis (i.e. Col1a1 and Col3a1) were upregulated, and histological examinations showed increased glomerular diameter in NX mice. Importantly, liraglutide treatment attenuated atherosclerosis (~40%, p < 0.05) and reduced kidney inflammation in NX mice. There was no effect of liraglutide on expression of fibrosis markers and/or kidney histology. This study suggests that liraglutide has beneficial effects in a mouse model of moderate uremia by reducing atherosclerosis and attenuating kidney inflammation.

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Section: Discussionsupporting

confidence: 83%

“…Ten-to-thirteen weeks old mice were subjected to 5/6 nephrectomy (NX), as previously described [7, 8] to induce mild to moderate uremia. Briefly, 5/6 nephrectomy was achieved in a 2-step operation.…”

Section: Methodsmentioning

confidence: 99%

Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

et al. 2016

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“…In experimental uremia plasma OP was increased and correlated positively with aortic atherosclerosis [48]. In our study we confirmed that plasma OP level is markedly increased in patients on regular HD but it does not relate to VS parameters.…”

Section: Discussionsupporting

confidence: 81%

The Impact of Osteocalcin, Osteoprotegerin and Osteopontin on Arterial Stiffness in Chronic Renal Failure Patients on Hemodialysis

Csiky

Sági

Peti³

et al. 2017

Kidney Blood Press Res

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Background/Aims: This cross-sectional study was designed to assess the relationship between vascular stiffness (VS) and bone-related proteins involved in the development of arteriosclerosis in patients on regular hemodialysis (HD). Methods: 68 consecutive patients in stable clinical condition who received regular HD in the FMC Dialysis Center, Pécs were included. VS parameters (carotid-femoral pulse wave velocity – PWV, aortic augmentation index - AIx) were determined by applanation tonometry (SphygmoCor, AtCor Medical, Sidney) and the routine latoratory test were completed with measurements of osteocalcin (OC), osteopontin (OP) and osteoprotegerin (OPG) by using commercially available ELISA kits. 35 heathcare workers served as controls. Results: In patients on regular HD PWV markedly increased and there was several-fold elevation in the interrelated bone-specific proteins (OC, OP, OPG). PWV was found to be independently associated only with OC (β:-0.25, p<0.029) and age (r=0.411,p<0.000), but risk factors for arterial calcification had significant impact on OC (systolic blood pressure, hsCRP, BMI), OPG (age, BMI) and OP (LDL-cholesterol). Conclusion: Except for OC, our results failed to document direct association of vascular lesion with OP and OPG, therefore their high circulating levels may be an epiphenomenon or they may have counter-regulatory role to attenuate the uremic calcification process.

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“…To our surprise, the gene expression analyses showed no uremia-mediated effects on expression of the SMC genes in the carotid control arteries in wt or Apoe −/− mice (apart from Tagln , which was downregulated by NX in control arteries in wt mice). This is in contrast to previous data in aortic SMCs 16, 18, 25, 26 , in which uremia altered mRNA expression of classical SMC marker genes. The gene expression differences observed in the previous vs the present study may thus relate to the different vascular beds examined, i.e.…”

Section: Discussioncontrasting

confidence: 99%

Uremia does not affect neointima formation in mice

Aarup

Nielsen

Bisgaard

et al. 2017

Sci Rep

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Atherosclerotic cardiovascular disease is a major complication of chronic kidney disease (CKD). CKD leads to uremia, which modulates the phenotype of aortic smooth muscle cells (SMCs). Phenotypic modulation of SMCs plays a key role in accelerating atherosclerosis. We investigated the hypothesis that uremia potentiates neointima formation in response to vascular injury in mice. Carotid wire injury was performed on C57BL/6 wt and apolipoprotein E knockout (Apoe −/−) mice two weeks after induction of uremia by 5/6 nephrectomy. Wire injury led to neointima formation and downregulation of genes encoding classical SMC markers (i.e., myocardin, α-smooth muscle actin, SM22-alpha, and smooth muscle myosin heavy chain) in both wt and Apoe −/− mice. Contrary to our expectations, uremia did not potentiate neointima formation, nor did it affect intimal lesion composition as judged from magnetic resonance imaging and histological analyses. Also, there was no effect of uremia on SMC marker gene expression in the injured carotid arteries, suggesting that there may be different effects of uremia on SMCs in different vascular beds. In conclusion, uremia does not accelerate neointima formation in response to wire injury of the carotid artery in mice.

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Osteopontin deficiency dampens the pro-atherogenic effect of uraemia

Abstract: The data suggest that OPN promotes development of uraemic atherosclerosis possibly by changing the phenotype of vascular smooth muscle cells.

Cited by 17 publications

References 46 publications

Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

The Impact of Osteocalcin, Osteoprotegerin and Osteopontin on Arterial Stiffness in Chronic Renal Failure Patients on Hemodialysis

Uremia does not affect neointima formation in mice

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