Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding

Abstract

Recent data suggested a causative role of uric acid (UA) in the development of renal disease, in which endothelial dysfunction is regarded as the key mechanism. Endothelial-to-mesenchymal transition (EndoMT) and shedding of the glycocalyx are early changes of endothelial dysfunction. We investigated whether UA induced EndoMT in HUVECs and an animal model of hyperuricemia fed with 2% oxonic acid for 4 wk. UA induced EndoMT in HUVECs with a generation of reactive oxygen species via the activation of membranous NADPH oxidase (from 15 min) and mitochondria (from 6 h) along with glycocalyx shedding (from 6 h), which were blocked by probenecid. GM6001, an inhibitor of matrix metalloproteinase, alleviated UA-induced glycocalyx shedding and EndoMT. Antioxidants including N-acetyl cysteine, apocynin, and mitotempo ameliorated EndoMT; however, they did not change glycocalyx shedding in HUVECs. In the kidney of hyperuricemic rats, endothelial staining in peritubular capillaries (PTCs) was substantially decreased with a de novo expression of a-smooth muscle actin in PTCs. Plasma level of syndecan-1 was increased in hyperuricemic rats, which was ameliorated by allopurinol. UA caused a phenotypic transition of endothelial cells via induction of oxidative stress with glycocalyx shedding, which could be one of the mechanisms of UA-induced endothelial dysfunction and kidney disease.

Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19

“…As shown in Fig. 2 , homeostasis is broken down, and vascular endothelial glycocalyx shedding/degradation occurs in conditions of cellular stress, ischemia/reperfusion injury [ 35 ], the presence of endotoxins [ 36 ], inflammatory mediators [ 37 ], atrial natriuretic peptide, excessive reactive oxygen species [ 38 ], hyperglycemia [ 39 , 40 ], high-salt intake [ 41 ], hypertension [ 42 ], familial hypercholesterolemia [ 43 ], and oxidized low-density lipoprotein (ox-LDL) [ 44 ]. Of note, rosuvastatin administration has been shown to partially restore damaged vascular endothelial cells in patients with heterozygous familial hypercholesterolemia [ 43 ].…”

“…Numerous anti-inflammatory mediators, such as TNF-α or its receptor inhibitor (etanercept) [ 37 ], allopurinol [ 38 ], sphingosine-1 phosphate (S1P) [ 89 ], and hydrocortisone, have been shown to have protective roles on the vascular endothelial glycocalyx [ 141 ]. Since these substances are expected to have anti-inflammatory and anti-oxidative effects, which impair vascular endothelial glycocalyx, they affects not only vascular endothelial cells but also vascular endothelial glycocalyx composition.…”

<p>Uric Acid and Arterial Stiffness</p>

“…41 A recent study has shown that UA can induce endothelial glycocalyx shedding which may contribute to increased oxidative stress and reduced nitric oxide bioavailability. 42 Besides its involvement in inflammation and oxidative stress, UA may also alter the natural turnover of non-cross -linked soluble elastin, thus reducing arterial wall distensibility. 43 Not only soluble UA but also the crystallized form of UA may cause vascular damage.…”

Research Advances in the Mechanisms of Hyperuricemia-Induced Renal Injury

“…These studies suggested that endothelial-origin myofibroblasts possibly contribute to the progression of glomerulosclerosis [ 68 , 70 ]. Recent research has demonstrated that UA induced the phenotype transition in HUVECs via induction of oxidative stress and glycocalyx shedding [ 71 ]. However, direct evidence is still lacking for the contribution of UA-induced EndoMT to glomerulosclerosis.…”