Capillary rarefaction: a missing link in renal and cardiovascular disease?

Steegh, Floor; Keijbeck, Anke; Hoogt, Patrick A. de; Rademakers, Timo; Houben, Alfons J. H. M.; Reesink, Koen D.; Stehouwer, Coen D. A.; Daemen, Mat J.A.P.; Peutz‐Kootstra, Carine J.

doi:10.1007/s10456-023-09883-8

Cited by 7 publications

(2 citation statements)

References 145 publications

(148 reference statements)

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“…[58,59] Future studies merging the donorderived approach described here with tissue-specific models will allow further exploration of organ-and tissue-specific complications of the uremia, such as the relative contributions of patient genetics and the uremic microenvironment to endothelial dysfunction and capillary rarefaction. [60] To provide a platform for generating microvessels from donorderived serum and cells, we evaluated the effects of serum on blood outgrowth endothelial cells (BOECs) due to the ability to derive BOECs from patient blood. [61] The use of BOECs will enable future work in which combinations of cells and serum can be used to test mechanistic hypotheses regarding the causes of increased CVD risk in patients with CKD.…”

Section: Discussionmentioning

confidence: 99%

Donor‐Derived Engineered Microvessels for Cardiovascular Risk Stratification of Patients with Kidney Failure

Rathod,

Aw,

Huang

et al. 2024

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Cardiovascular disease is the cause of death in ≈50% of hemodialysis patients. Accumulation of uremic solutes in systemic circulation is thought to be a key driver of the endothelial dysfunction that underlies elevated cardiovascular events. A challenge in understanding the mechanisms relating chronic kidney disease to cardiovascular disease is the lack of in vitro models that allow screening of the effects of the uremic environment on the endothelium. Here, a method is described for microfabrication of human blood vessels from donor cells and perfused with donor serum. The resulting donor‐derived microvessels are used to quantify vascular permeability, a hallmark of endothelial dysfunction, in response to serum spiked with pathophysiological levels of indoxyl sulfate, and in response to serum from patients with chronic kidney disease and from uremic pigs. The uremic environment has pronounced effects on microvascular integrity as demonstrated by irregular cell–cell junctions and increased permeability in comparison to cell culture media and healthy serum. Moreover, the engineered microvessels demonstrate an increase in sensitivity compared to traditional 2D assays. Thus, the devices and the methods presented here have the potential to be utilized to risk stratify and to direct personalized treatments for patients with chronic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Donor‐Derived Engineered Microvessels for Cardiovascular Risk Stratification of Patients with Kidney Failure

Rathod,

Aw,

Huang

et al. 2024

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“…In patients with hypertension, the presence of EVs indicating podocyte injury and peritubular capillary injury is detected [36]. The endothelial cells derived EVs released from peritubular capillaries were checked in the primary and renovascular hypertension patients' urine, with the density of EVs directly associated with clinical parameters and the scarcity of capillaries, but was inversely proportional to renal perfusion [37]. Therefore, the change of urinary EVs in hypertensive patients can be regarded as an early marker of renal injury caused by peritubular capillary injury, and it will change with the improvement of renal function after drug treatment in patients with primary and renovascular hypertension (Figure 1).…”

Section: Extracellular Vesicles As Delivery Vans In Cell-cell Communi...mentioning

confidence: 99%

Extracellular Vesicles in Kidney Disease

2024

Extracellular Vesicles - Applications and Therapeutic Potential

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The kidney is the mainly apparatus in the human body, with a complex organizational structure and diverse pathological changes closely related to other organs. Extracellular vesicles are vesicles with diameters ranging from tens of nanometers to several micrometers, originating from multiple intracellular vesicles or local cell membranes. They carry various information from the source cells and operate between various cells in the kidney and extrarenal organs, conveying substances between cells. They play a large part in signal transmission within the kidney and between the kidney and other organs. Detecting changes in extracellular vesicles and their cargo can monitor both renal neoplastic and nonneoplastic diseases. Extracellular vesicles derived from various stem cells, loaded with bioactive substances, can be applied to some extent to treat kidney diseases. Bioengineering drugs using extracellular vesicles as carriers are also playing an increasingly big role in treating kidney diseases. Research on extracellular vesicles has achieved certain results and has some preclinical applications, but there is still a process for large-scale and widespread application.

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Investigating the cause of cardiovascular dysfunction in chronic kidney disease: capillary rarefaction and inflammation may contribute to detrimental cardiovascular outcomes

Beikoghli Kalkhoran,

Basalay,

et al. 2024

Basic Res Cardiol

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Myocardial ischemia–reperfusion (IR) injury is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD). The most frequently used and representative experimental model is the rat dietary adenine-induced CKD, which leads to CKD-associated CVD. However, the continued intake of adenine is a potential confounding factor. This study investigated cardiovascular dysfunction following brief adenine exposure, CKD development and return to a normal diet. Male Wistar rats received a 0.3% adenine diet for 10 weeks and normal chow for an additional 8 weeks. Kidney function was assessed by urinalysis and histology. Heart function was assessed by echocardiography. Sensitivity to myocardial IR injury was assessed using the isolated perfused rat heart (Langendorff) model. The inflammation profile of rats with CKD was assessed via cytokine ELISA, tissue histology and RNA sequencing. Induction of CKD was confirmed by a significant increase in plasma creatinine and albuminuria. Histology revealed extensive glomerular and tubular damage. Diastolic dysfunction, measured by the reduction of the E/A ratio, was apparent in rats with CKD even following a normal diet. Hearts from rats with CKD had significantly larger infarcts after IR injury. The CKD rats also had statistically higher levels of markers of inflammation including myeloperoxidase, KIM-1 and interleukin-33. RNA sequencing revealed several changes including an increase in inflammatory signaling pathways. In addition, we noted that CKD induced significant cardiac capillary rarefaction. We have established a modified model of adenine-induced CKD, which leads to cardiovascular dysfunction in the absence of adenine. Our observations of capillary rarefaction and inflammation suggest that these may contribute to detrimental cardiovascular outcomes.

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Capillary rarefaction: a missing link in renal and cardiovascular disease?

Cited by 7 publications

References 145 publications

Donor‐Derived Engineered Microvessels for Cardiovascular Risk Stratification of Patients with Kidney Failure

Donor‐Derived Engineered Microvessels for Cardiovascular Risk Stratification of Patients with Kidney Failure

Extracellular Vesicles in Kidney Disease

Investigating the cause of cardiovascular dysfunction in chronic kidney disease: capillary rarefaction and inflammation may contribute to detrimental cardiovascular outcomes

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