Elevated Endostatin Expression Is Regulated by the pIgA Immune Complex and Associated with Disease Severity of IgA Nephropathy

Abstract

<b><i>Background/Aims:</i></b> Renal vascular injury accounts for the poor outcomes of patients with IgA nephropathy (IgAN). In this study, we investigated whether endostatin, a potent inhibitor of angiogenesis, is associated with IgAN. <b><i>Methods:</i></b> Serum endostatin levels were detected in patients with IgAN, disease controls, and healthy controls, and the correlation among endostatin and clinicopathologic manifestations, as well as prognosis in patients with IgAN, was analyzed. In addition, serum endostatin levels were compared in patients “before” and “after” treatment. Data on endostatin expression in the renal interstitium of patients with IgAN were downloaded and analyzed from the GSE35489 array in the GEO database. The poly-IgA1 (pIgA) immune complex is widely recognized as the “trigger” of IgAN initiation. pIgA in the plasma of patients was extracted and used to stimulate human glomerular endothelial cells (GECs). Endostatin, IL-6, and CXCL1 in the cell supernatant were detected by ELISA kits. <b><i>Results:</i></b> We found that serum endostatin levels were significantly increased in patients with IgAN, as was endostatin expression in the renal interstitium. Patients with IgAN were divided into 2 groups according to the median value. The high endostatin expression group had significantly higher levels of serum creatinine and BUN and more severe tubular/interstitial damage. Moreover, patients with arteriolar injury and endothelial cell proliferation had higher serum endostatin levels. Patients with high serum endostatin levels had poor prognosis. According to the in vitro experiment, the GEC apoptosis rate and the supernatant levels of endostatin, IL-6, and CXCL1 were significantly increased following pIgA stimulation. <b><i>Conclusion:</i></b> Our study found that elevated endostatin expression was associated with disease severity and poor prognosis in patients with IgAN and can be upregulated by pIgA, but how it participates in the pathogenesis of IgAN deserves further exploration.

Molecular insight in intrarenal inflammation affecting four main types of cells in nephrons in IgA nephropathy

“…Clinical data have reported that damage of endothelium in IgAN with loss of endothelial cells is very common. Dissection of glomerular endothelial cells from the basal membrane, formation of endothelial cavitation, and insertion of the basal membrane was also observed in rat models with IgAN (71,72).…”

“…MiR-223 addition could inhibit NF-κB and STAT3 nuclear translocation, thereby alleviating endothelial cell proliferation, ICAM-1 expression, and monocyte adhesion on the endothelium. Another in vitro experiment demonstrated that elevated expression of endostatin, an endogenous angiogenesis inhibitor, and IL-6 with decreased cell proliferation activity was found in cultured endothelial cells after polymeric IgA stimulation ( 72 ). As direct stimulation of IL-6 enhances endothelial cell proliferation, it is reasonable to hypothesize that endostatin secreted by endothelial cells plays a self-protective role in cell proliferation while IL-6 from mesangial cells stimulated by Gd-IgA deposition enhances endothelial cell proliferation, and they collaboratively result in endothelial cell loss and hyperpermeability of endothelium finally.…”

Independent Prognostic and Predictive Role of Interstitial Macrophages in Kidney Biopsies of IgA Nephropathy Patients

“…It is well known that proteinuria stimulates tubular epithelial cells to release the macrophage chemoattractant protein 1 (MCP-1/CCL2) and cytokines activating macrophages in vitro and in vivo [ 38 , 39 , 40 , 41 ]. In IgAN, MCP1 is highly expressed by tubular epithelial cells [ 20 , 21 ], and is detected in the urine [ 23 , 24 , 26 , 27 ]. Furthermore, its urinary level correlates with tubulointerstitial inflammation, severity of histopathological lesions, and adverse prognosis [ 23 , 24 , 26 ].…”

“…Interstitial macrophage infiltration in IgAN kidney biopsies has been associated with poor prognosis and severity of the disease since 2006 [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]; however, this parameter is not included in the Oxford classification. Disease-specific urinary biomarkers can be useful as diagnostic and/or prognostic tools, potentially avoiding second biopsies [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Extracellular Vesicles Derived from Endothelial Progenitor Cells Protect Human Glomerular Endothelial Cells and Podocytes from Complement- and Cytokine-Mediated Injury

“…The relevance of angiogenesis in the glomerular filtration barrier damage in the course of inflammatory diseases such as glomerulonephritis has been demonstrated in different experimental models [ 56 , 57 ]: moreover, a potential role of angiogenesis has been recently described also in human glomerular diseases [ 58 , 59 ]. Several mediators, including Vascular Endothelial Growth Factor (VEGF-A) and nitric oxide (NO) have been shown to play a pivotal role in glomerular capillary repair during inflammatory diseases [ 60 , 61 ].…”