Endothelial dysfunction is a superinducer of syndecan-4: fibrogenic role of its ectodomain.

Syndecan-4 (Synd4) is a member of the membrane-spanning, glycocalyx-forming proteoglycan family. It has been suggested that Synd4 participates in renal fibrosis. We compared wild-type and fibrosis-prone endothelial sirtuin 1-deficient (Sirt1endo-/-) mice, the latter being a model of global endothelial dysfunction. We performed mass spectrometry analysis, which revealed that Synd4 was highly enriched in the secretome of renal microvascular endothelial cells obtained from Sirt1endo-/- mice upon stimulation with transforming growth factor-ß1; notably, all detectable peptides were confined to the ectodomain of Synd4. Elevated Synd4 was due to enhanced NF-κB signaling in Sirt1endo-/- mice, while its shedding occurred as a result of oxidative stress in Sirt1 deficiency. Synd4 expression was significantly enhanced after unilateral ureteral obstruction compared with contralateral kidneys. Furthermore, hyperplasia of renal myofibroblasts accompanied by microvascular rarefaction and overexpression of Synd4 were detected in Sirt1endo-/- mice. The ectodomain of Synd4 acted as a chemoattractant for monocytes with higher levels of macrophages and higher expression levels of Synd4 in the extracellular matrix of Sirt1endo-/- mice. In vitro, ectodomain application resulted in generation of myofibroblasts from cultured renal fibroblasts, while in vivo, subcapsular injection of ectodomain increased interstitial fibrosis. Moreover, the endothelial glycocalyx was reduced in Sirt1endo-/- mice, highlighting the induction of Synd4 occurring in parallel with the depletion of its intact form and accumulation of its ectodomain in Sirt1endo-/- mice. On the basis of our experimental results, we propose that it is the Synd4 ectodomain per se that is partially responsible for fibrosis in unilateral ureteral obstruction, especially when it is combined with endothelial dysfunction. NEW & NOTEWORTHY Our findings suggest that endothelial dysfunction induces the expression of syndecan-4 via activation of the NF-κB pathway. Furthermore, we show that syndecan-4 is shed to a greater amount because of increased oxidative stress in dysfunctional endothelial cells and that the release of the syndecan-4 ectodomain leads to tubulointerstitial fibrosis.

The third path of tubulointerstitial fibrosis: aberrant endothelial secretome.

The secretome, defined as a portion of proteins secreted by specific cells to the extracellular space, secures a proper microenvironmental niche not only for the donor cells, but also for the neighboring cells, thus maintaining tissue homeostasis. Communication via secretory products exists between endothelial cells and fibroblasts, and this local mechanism maintains the viability and density of each compartment. Endothelial dysfunction, apart from obvious cell-autonomous defects, leads to the aberrant secretome, which predisposes fibroblasts to acquire a myofibroblastic fibrogenic phenotype. In our recent profiling of the secretome of such dysfunctional profibrogenic renal microvascular endothelial cells, we identified unique profibrogenic signatures, among which we detected ligands of Notch and Wnt-ß-catenin pathways. Here, we stress the role of reprogramming cues in the immediate microenvironment of (myo)fibroblasts and the contribution of the endothelial secretome to the panoply of instructive signals in the vicinity of fibroblasts. We hope that this brief overview of endothelial-fibroblast communication in health and disease will lead to eventual unbiased proteomic mapping of individual secretomes of glomerular and tubular epithelial cells, pericytes, and podocytes through reductionist approaches to allow for the synthetic creation of a complex network of secretomic signals acting as reprogramming factors on individual cell types in the kidney. Knowledge of profibrogenic and antifibrogenic signatures in the secretome may garner future therapeutic efforts.

Dilatation of the spinal epidural venous plexus in patients with prominent epidural fat.

OBJECTIVE: The purpose of this study was to evaluate the correlation between the dilatation of the spinal epidural venous plexus (SEVP) and the amount of epidural fat (EF). METHODS: Between January 2007 and January 2012, 116 patients with prominent EF and 116 control subjects without prominent EF were included in this study. On the lumbar MR images, we graded the amount of EF and counted the number of vertebrae to determine the longitudinal extent of the EF. We evaluated and classified the dilatation of the SEVP and the degree of central canal stenosis. RESULTS: SEVP dilatation significantly differed between the group with prominent EF and the control group (p-value < 0.0001). Dilatation of the anterior epidural veins was seen in all subjects with dilatation of the SEVP. In the group with prominent EF, 80 (69%) patients showed dilatation of the posterior epidural veins. The longitudinal extent of the prominent EF was significantly associated with the grade of SEVP dilatation. The EF grade and the sum of the EF grades of all levels of the lumbar spine with prominent EF showed a positive correlation with the grade of central canal stenosis (r = 0.421 and r = 0.347, respectively; p-value < 0.0001). CONCLUSION: The dilatation of epidural veins was statistically significant in patients with prominent EF. The detection of SEVP dilatation on MR images may be helpful for spine surgery involving the epidural space. ADVANCES IN KNOWLEDGE: Owing to the risk of bleeding, the detection of SEVP dilatation on MRI may be helpful when considering decompression surgery with a posterior approach for spinal stenosis caused by prominent EF.