The soluble VEGF receptor sFlt-1 contributes to endothelial dysfunction in IgA nephropathy

Abstract

Endothelial injury is a common manifestation in IgA nephropathy (IgAN). After the previous identification of the upregulated soluble fms-like tyrosine kinase-1 (sFlt-1) correlated with endothelial injury in IgAN, in the present study, we further explored the role of sFlt-1 in endothelial injury in IgAN. We enrolled 72 patients with IgAN and detected the sFlt-1 levels. The polymeric IgA1 (pIgA1) complexes were isolated from the pooled plasma samples of another 10 patients with IgAN. Apoptosis proteins were detected in cultured human umbilical vein endothelial cells (HUVECs) with the stimulation of recombinant sFlt-1 or the caspase-9 inhibitor Z-LEHD-FMK. We identified there were positive correlations between sFlt-1 and IgA-IgG complex as well as vWF levels in patients with IgAN. The sFlt-1 levels in HUVECs were significantly upregulated by pIgA1 complex derived from IgAN patients in a concentration-dependent manner. The proliferation ability of HUVECs was damaged when stimulated with sFlt-1 protein in a time-and dose-dependent manner. And the apoptosis rate was up-regulated significantly as the stimulation concentrations of sFlt-1 increased. We found sFlt-1 challenge could significantly increase the expression of vWF. In addition, sFlt-1 increased the levels of caspase-9, caspase-3, Bax and mitochondrial membrane potential; facilitated the release of cytochrome C from mitochondria to cytoplasma. In contrast, Z-LEHD-FMK attenuated high sFlt-1-induced HUVECs apoptosis. In conclusion, our study demonstrated that sFlt-1 expression was up-regulated by the challenge of pIgA1 complex derived from patients with IgAN. Furthermore, increased sFlt-1 facilitated human umbilical vein endothelial cells apoptosis via the mitochondrial-dependent pathway.

RETRACTED: Oxidized LDL Causes Endothelial Apoptosis by Inhibiting Mitochondrial Fusion and Mitochondria Autophagy

“…Irreparable mitochondrial damage will release pro-apoptotic proteins into the cytoplasm and initiate the mitochondria-mediated death pathway. Endothelial mitochondrial dysfunction has been linked to several diseases such as diabetes-induced microvascular injury, cerebral ischemia-reperfusion injury ( Zhang et al, 2020 ), nephropathy ( Zhai et al, 2020 ), peripheral artery disease ( Park et al, 2020 ), and pulmonary artery hypertension ( Wang et al, 2020 ). Many researches have observed the role of mitochondrial damage in triggering endothelial dysfunction upon ox-LDL treatment ( Li et al, 2018 , Li et al, 2020 ; Yuan et al, 2019 ; Xie et al, 2020 ), suggesting an urgent need for therapies that protect endothelial mitochondria in order to reduce atherosclerosis development.…”

Progesterone Induced Blocking Factor Reduces Hypertension and Placental Mitochondrial Dysfunction in Response to sFlt-1 during Pregnancy

“…[ 43 ]. Zhai et al showed that the proliferation of HUVECs was damaged and apoptosis was up-regulated when stimulated by sFlt-1, which further demonstrates that sFlt-1 contributes to endothelial dysfunction [ 44 ].…”

Based on Network Pharmacology Tools to Investigate the Mechanism of Tripterygium wilfordii Against IgA Nephropathy

“…In addition, TwHF extracts contained novel inhibitors of MMP including MMP9 thus might have therapeutic potential in arthritis and other conditions associated with increased MMPs like IgAN ( 38 , 39 ). CASP3 is known as a representative effector of apoptosis, cleaved caspase-3 active fragment could mediate apoptosis in endothelial cells ( 40 ). PTGS2 also known as cyclooxygenase 2 (COX2), is the key enzyme in prostaglandin biosynthesis, and is responsible for the prostanoid biosynthesis involved in inflammation and mitogenesis.…”