Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness

Abstract

Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean ± SD 156.6 ± 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 ± 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe−/− cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.

Significance of Soluble CD93 in Type 2 Diabetes as a Biomarker for Diabetic Nephropathy: Integrated Results from Human and Rodent Studies

“…Specific genetic loci that affect the microvascular endothelial cells in glomeruli might contribute to this phenomenon [22,[26][27][28][29][30]. Although the association between sCD93 and cardiovascular disease has been studied, the results are complex, depending on the study population and the target vessels [6,7,17,31]. In our diabetic patients, there was no difference in macrovascular complications, such as coronary artery disease, peripheral artery disease, and CVA, between the low and high serum sCD93 groups.…”

“…First, the number of human study subjects was relatively small to perform additional subgroup analyses. Previously, several studies measured sCD93 in a larger number of human subjects compared with the current study [7,17,31]. However, no previous report investigated the clinical implication of sCD93 in a DN-centric view based on the eGFR and the ACR, which is the novel part of our study despite the relatively small number of participants.…”

“…In addition, circulating levels of several inflammatory mediators such as C-reactive protein, interleukin-6, and beta-2-microglobulin are closely associated with DN [37][38][39], and to investigate the association between these previous pro-inflammatory markers and sCD93 levels would give additional information on how to interpret the clinical implication of sCD93. Third, the level of sCD93 was mostly measured using plasma or serum in humans [4,7,9,31], and not measured using urine samples in our human study. As urinary sCD93 levels were significantly increased in the db/db mice compared with db/m+ mice in vivo, further studies using human urine samples to measure sCD93 levels could confirm the clinical utility of urinary sCD93 levels as a biomarker of DN.…”

The potential role of chemotaxis and the complement system in the formation and progression of thoracic aortic aneurysms inferred from the weighted gene coexpression network analysis

“…It was previously found that murine CD93 contributes to the removal of apoptotic cells in vivo [ 37 ]. Interestingly, Strawbridge et al demonstrated the function of soluble CD93 (sCD93) in glucometabolic regulation, and lower sCD93 levels might be related to type 2 diabetes patients who have a higher cardiovascular disease risk [ 38 ]. However, no research has focused on the mechanism of action of CD93 molecules in aneurysmal diseases.…”

The relationship of indoxyl sulfate and p-cresyl sulfate with target cardiovascular proteins in hemodialysis patients

“…It is over-expressed during inflammation, and the soluble form (soluble CD93) is increased in various inflammatory conditions. Soluble CD93 is associated with premature myocardial infarction, coronary artery disease, and other inflammatory conditions [38][39][40] , with reduced levels of the soluble CD93 related to metabolic dysregulation 41 . Thus, the release of soluble CD93 has been implicated in response to stressors, such as inflammatory, immune, and angiogenic mediators.…”