The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function

Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in the remodeling process. Under uremic conditions, VSMCs can switch from a contractile phenotype to a synthetic phenotype, and undergo abnormal proliferation, migration, senescence, apoptosis, and calcification. A growing body of data from experiments in vitro and animal models suggests that uremic toxins (such as inorganic phosphate, indoxyl sulfate and advanced-glycation end products) may directly impact the VSMCs’ physiological functions. Chronic, low-grade inflammation and oxidative stress—hallmarks of CKD—are also strong inducers of VSMC dysfunction. Here, we review current knowledge about the impact of uremic toxins on VSMC function in CKD, and the consequences for pathological vascular remodeling

The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function

Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in the remodeling process. Under uremic conditions, VSMCs can switch from a contractile phenotype to a synthetic phenotype, and undergo abnormal proliferation, migration, senescence, apoptosis, and calcification. A growing body of data from experiments in vitro and animal models suggests that uremic toxins (such as inorganic phosphate, indoxyl sulfate and advanced-glycation end products) may directly impact the VSMCs’ physiological functions. Chronic, low-grade inflammation and oxidative stress—hallmarks of CKD—are also strong inducers of VSMC dysfunction. Here, we review current knowledge about the impact of uremic toxins on VSMC function in CKD, and the consequences for pathological vascular remodeling

Aortic stenosis in patients with kidney failure: Is there an advantage for a PD-first policy ?

Aortic stenosis (AS) is the most common valvular disease. It is twice as prevalent in patients with kidney failure as compared to the general population. In addition, AS progresses at a faster rate and is associated with a higher risk of death and poorer quality of life in patients on dialysis. Chronic kidney disease-mineral and bone disorder (CKD-MBD), inflammation, and hemodynamic disturbances contribute to the pathophysiology and progression of AS. Whether the type of dialysis modality, that is, hemodialysis (HD) versus peritoneal dialysis (PD), has a differential impact on the development and progression of AS in patients with kidney failure remains debated. Recent data indicate that the prevalence of valvular calcifications might be lower and the development of AS delayed in PD patients, as compared to those treated with HD. This could be accounted for by several mechanisms including reduced valvular shear stress, better preservation of residual kidney function (with better removal of protein-bound uremic toxins and CKD-MBD profile), and lower levels of systemic inflammation. Given the high morbidity and mortality rates related to interventional procedures in the population with kidney failure, surgical and transcatheter aortic valve replacement should be considered in selected patients with severe AS. Strategies slowing down the progression of aortic valve remodeling should remain the cornerstone in the management of individuals with kidney failure and mild to moderate AS. This review explores the potential benefits of PD in patients with kidney failure and AS and provides some clues to help clinicians in the decision-making process when options for kidney replacement therapy are considered in patients with AS

The Impact of Uremic Toxins on Cerebrovascular and Cognitive Disorders

Individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia. Stroke is also highly prevalent in this population and is associated with a higher risk of neurological deterioration, in-hospital mortality, and poor functional outcomes. Evidence from in vitro studies and in vivo animal experiments suggests that accumulation of uremic toxins may contribute to the pathogenesis of stroke and amplify vascular damage, leading to cognitive disorders and dementia. This review summarizes current evidence on the mechanisms by which uremic toxins may favour the occurrence of cerebrovascular diseases and neurological complications in CKD

Relationship between bone marrow adipose tissue and kidney function in postmenopausal women

Introduction: Bone marrow adipose tissue (BMAT) is associated with aging, osteoporosis, and chronic kidney disease (CKD). To date, the association between BMAT and kidney function in postmenopausal women has not been thoroughly investigated. The main purpose of this study was to determine whether a relationship exists between proton density fat fraction (PDFF) and kidney function in postmenopausal women. Methods: We investigated the cross-sectional association between estimated glomerular filtration rate (eGFR) – calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation – and PDFF – measured at the lumbar spine and proximal femur using Water Fat Imaging (WFI) MRI – in 199 postmenopausal women from the ADIMOS cohort study. We also performed DXA scans and laboratory measurements of sclerostin and c-terminal Fibroblast Growth Factor 23 (cFGF23). Results: Participants' mean age was 67.5 (standard deviation, SD 10.0) years. Their median eGFR was 85.0 (interquartile range, IQR 72.2–95.0) ml/min/1.73 cm2, and their mean lumbar spine PDFF was 57.9 % (SD 9.6). When classified by eGFR-based CKD stages, 41.7 % of the cohort had an eGFR ≥ 90 (n = 83), 47.2 % had an eGFR of 60–89.9 (n = 94), and 11.1 % had an eGFR of 30–59.9 (n = 22). Participants with eGFR ≥ 90 had a lower lumbar spine PDFF than those with eGFR 60–89.9 (mean 55.8 % (9.8) vs. 58.9 % (9.0), p = 0.031) and those with eGFR 30–59.9 (55.8 % (9.8) vs. 60.8 % (9.8), p = 0.043). However, the differences did not remain significant after adjusting for predetermined confounders, including age, diabetes, Charlson comorbidity index, recent history of fragility fracture, appendicular lean mass, and lumbar spine BMD. The inclusion of sclerostin and/or cFGF23 as suspected mediators did not alter the findings. When proximal hip imaging-based PDFF was considered, no significant differences were found between the eGFR categories in the unadjusted and adjusted analyses. Conclusion: No evidence of an association between kidney function and bone marrow adiposity was found either in the lumbar spine or proximal femur in a cohort of postmenopausal women

#1409 Enhancer of zeste homolog 2 (EZH2) as a new therapeutic target to prevent indoxyl-sulfate-induced aortic valve calcification

International audienceBackground and Aims Calcific aortic valve disease (CAVD) is highly prevalent in chronic kidney disease (CKD) patients and is associated with a poor prognosis. To date, there is no pharmacological treatment to slow down this process. Our group recently reported that indoxyl-sulfate (IS) -induced IL-6 secretion in human interstitial valvular cells (hVICs) promotes their osteogenic transition and calcification in an autocrine manner. Preliminary data suggest that IS also influences macrophage secretion of IL-6. Whether this phenomenon affects the hVICs mineralization remains to be elucidated. In this context, the epigenetic enzyme Enhancer of Zeste Homolog 2 (EZH2), a key modulator of macrophages’ inflammation, may represent an interesting therapeutic target. Thus, this work aimed to verify whether IS-induced macrophages’ secretion of IL-6 modulates hVICs mineralization, and to determine whether EZH2 is involved in this inflammatory process. Method THP1-derived macrophages were exposed to increasing concentrations of IS (IS normal [Isn]: 0.5 μg/mL, IS uremic [Isu]: 37 μg/mL, IS intermediate [int]: 100 μg/mL or IS maximum [Ismax]: 233 μg/mL) in the presence or absence of an EZH2 inhibitor called GSK-343 (5µM). EZH2 expression and activity (evidenced by the trimethylation of the lysine 27 of the histones H3 (H3K27me3)) were assessed by western blot. Macrophages’ inflammatory potential was checked by RT-qPCR, western blot and Elisa. The impact of macrophages exposed or not to IS and/or GSK-343 on hVICs osteogenic transition was evaluated using conditioned media. HVICs osteogenic transition was assessed following runx2 expression by qRT-PCR and western blot. Mineralization was quantified by the o-cresolphthalein method. Results IS induced macrophages secretion of IL-1β, IL-6, CCL2 and TNF-α. Conditioned media from IS-polarized macrophages promoted a 6-fold increase in hVICs calcification and favored their osteogenic transition as evidenced by increased runx2 expression. IL-6 was the only cytokine able to promote runx2 expression in hVICs, confirming the importance of this specific cytokine in the process. Exposure to IS upregulated macrophages’ expression EZH2, an effect blocked by GSK-343. If GSK-343 did not affect IS-induced macrophages’ secretion of IL-1β, CCL2 and TNF-α, it efficiently blocked the secretion of IL-6 and subsequent induction of runx2 in hVICs. In this model, neither IS, nor GSK-343 modulated macrophages’ H3K27me3, suggesting that EZH2 may act as a transcriptional factor for IL-6 through its non-canonical pathway. In this latter, EZH2 is thought to promote inflammation by binding to p65, rather than through its trimethylation activity. In line with this hypothesis, exposure to IS promoted EZH2 and p65 nuclear translocation in the meantime as well as their co-immunoprecipitation, two phenomena blocked by GSK343. Conclusion This work demonstrates that IS-induced macrophages’ secretion of IL-6 promotes hVICs osteogenic transition and mineralization. Our data suggest that IL-6 secretion in response to IS depends on the EZH2-p65 pathway. The fact that GSK-343 can block this mechanism sheds light on EZH2 as a new therapeutic target to prevent CAVD in CKD patients

Cellular and molecular mechanisms associated with ischemic stroke severity in female mice with chronic kidney disease

Abstract Ischemic stroke is highly prevalent in chronic kidney disease (CKD) patients and has been associated with a higher risk of neurological deterioration and in-hospital mortality. To date, little is known about the processes by which CKD worsens ischemic stroke. This work aimed to investigate the cellular and molecular mechanism associated with ischemic stroke severity in an in vivo model of CKD. CKD was induced through right kidney cortical electrocautery in 8-week-old female C57BL/6 J mice followed by left total nephrectomy. Transient middle cerebral artery occlusion (tMCAO) was performed 6 weeks after left nephrectomy. Twenty-four hours after tMCAO, the infarct volumes were significantly wider in CKD than in SHAM mice. CKD mice displayed decreased neuroscore, impaired ability to remain on rotarod device, weaker muscular strength and decreased prehensile score. Apoptosis, neuronal loss, glial cells recruitment and microglia/macrophages M1 signature genes CD32, CD86, IL-1β, IL-6, MCP1 and iNOS were significantly increased within ischemic lesions of CKD mice. This effect was associated with decreased AMP kinase phosphorylation and increased activation of the NFΚB pathway. Pharmacological targeting of AMP kinase activity, which is known to block microglia/macrophages M1 polarization, appears promising to improve stroke recovery in CKD