Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Abstract

BackgroundDysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia‐induced endothelial damage and the extent to which this was dependent on increased α‐Klotho concentrations.Methods and ResultsIn a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial‐gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α‐Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real‐time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro‐permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial‐cadherin–based cell‐cell junctions and diminished F‐actin stress fiber organization, preventing the formation of endothelial intracellular gaps.ConclusionsOur results demonstrate that paricalcitol attenuates the CKD‐induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell‐cell interactions.

Immunologic Effects of Vitamin D on Human Health and Disease

“…Activation of VDR also activates eNOS via the phosphoinositide 3-kinase/protein kinase b (PI3K/Akt) pathway that triggers phosphorylation of serine-1779 on eNOS [ 41 ]. Furthermore, Cuenca et al [ 42 ] showed in a uremic rat model using the immunofluorescence technique that 1,25(OH) 2 D 2 promoted vascular endothelial-cadherin-based cell–cell junctions and inhibited F-actin stress fiber organization, thereby preventing the formation of endothelial intracellular gaps and attenuating endothelial damage in the presence of chronic kidney disease. Taken together, it is evident that vitamin D and its metabolites exert pleiotropic effects on the vascular endothelium that are protective against vascular dysfunction and tissue injury as a result of local and systemic inflammation.…”

How Does Endothelial Permeability Affect the Development of Juvenile Idiopathic Arthritis? Vascular Endothelial Cadherin as a Promising New Tool Helpful in the Diagnostic Process

“…Additionally, literature data suggested potential influence of vitamin D on vascular permeability. In the study published by Vila Cuenca et al [ 25 ], paricalcitol (which is an active vitamin D analogue) directly mediated endothelial integrity in vitro by enforcing cell-cell adhesion. However, in the recent study, vitamin D insufficiency did not influence VE-cadherin levels (data not shown).…”

How do Uremic Toxins Affect the Endothelium?

“…In CKD patients, studies have detected disruptions to the structure of the endothelial monolayer in renal arteries [ 13 , 75 ]. Loss of endothelial integrity and enhanced permeability are also seen in the aortic endothelium of nephrectomized rats, an animal model of CKD [ 76 , 77 ]. In vitro, PCS, IS, and uremic serum reduced the transendothelial electrical resistance (TEER), which indicates an increase in endothelial permeability [ 75 , 78 , 79 ].…”

“…The impairment of the endothelial barrier induced by uremic toxins contributes to the increased permeability that is associated with vascular injury and the development of CVD, such as atherosclerosis ( Figure 2 ) [ 77 , 84 ]. However, studies have found that vitamin D supplementation attenuated the effects of uremic toxins on endothelial disruption in HUVECs, and in nephrectomized rats [ 76 , 79 ].…”