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1.
Cell Mol Life Sci ; 72(16): 3157-71, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25790939

ABSTRACT

Childhood nephrotic syndrome is mainly caused by minimal change disease which is named because only subtle ultrastructural alteration could be observed at electron microscopic level in the pathological kidney. Glomerular podocytes are presumed to be the target cells whose protein sieving capability is compromised by a yet unidentified permeability perturbing factor. In a cohort of children with non-hereditary idiopathic nephrotic syndrome, we found the complement fragment C5a was elevated in their sera during active disease. Administration of recombinant C5a induced profound proteinuria and minimal change nephrotic syndrome in mice. Purified glomerular endothelial cells, instead of podocytes, were demonstrated to be responsible for the proteinuric effect elicited by C5a. Further studies depicted a signaling pathway involving Rho/Rho-associated kinase/myosin activation leading to endothelial cell contraction and cell adhesion complex breakdown. Significantly, application of Rho-associated kinase inhibitor, Y27632, prevented the protein leaking effects observed in both C5a-treated purified endothelial cells and mice. Taken together, our study identifies a previously unknown mechanism underlying nephrotic syndrome and provides a new insight toward identifying Rho-associated kinase inhibition as an alternative therapeutic option for nephrotic syndrome.


Subject(s)
Amides/pharmacology , Complement C5a/adverse effects , Nephrotic Syndrome/complications , Proteinuria/drug therapy , Pyridines/pharmacology , Recombinant Proteins/adverse effects , rho-Associated Kinases/antagonists & inhibitors , Analysis of Variance , Animals , Blotting, Western , Child , Complement C5a/metabolism , Cytokines/analysis , DNA Primers/genetics , Endothelial Cells/metabolism , Endothelial Cells/ultrastructure , Humans , Immunoenzyme Techniques , Kidney Glomerulus/cytology , Kidney Glomerulus/drug effects , Mice , Mice, Inbred ICR , Microscopy, Electron, Transmission , Proteinuria/etiology , Proteinuria/metabolism , Recombinant Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , rho-Associated Kinases/metabolism
2.
Fertil Steril ; 100(5): 1476-85, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24012198

ABSTRACT

OBJECTIVE: To determine whether a tumor necrosis factor-α (TNF-α) inhibitor can reduce the embryotoxicity of the peritoneal fluid (PF) of women with endometriosis. DESIGN: Experimental clinical study. SETTING: University hospital. PATIENT(S): Twelve women with chocolate cysts and 12 control women without endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We collected the PF from patients with chocolate cysts (CH-PF) and patients without endometriosis (N-PF) during laparoscopic surgery. For the in vitro studies, development and apoptosis were evaluated in two-cell stage mouse embryos after incubation with CH-PF and N-PF, with or without a TNF-α inhibitor. RESULT(S): We found that CH-PF significantly decreased the rate of blastocyst development and increased the percentage of apoptotic cells in the embryos. Cytokine assays showed that the concentrations of several cytokines, including TNF-α, were higher in embryos incubated with CH-PF than in those incubated with N-PF. Furthermore, the treatment of embryos with TNF-α retarded development and induced apoptosis. Important, adalimumab, a TNF-α inhibitor, effectively abrogated the embryotoxicity that was induced by CH-PF. CONCLUSION(S): These data collectively highlight the crucial role of TNF-α in CH-PF-induced embryotoxicity and suggest that TNF-α inhibitors may be potential therapeutic agents for treating endometriosis-induced infertility.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Ascitic Fluid/immunology , Blastocyst/drug effects , Endometriosis/immunology , Ovarian Cysts/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Adult , Animals , Apoptosis/drug effects , Blastocyst/immunology , Blastocyst/pathology , Case-Control Studies , Embryo Culture Techniques , Embryonic Development/drug effects , Endometriosis/complications , Female , Humans , Infertility, Female/drug therapy , Infertility, Female/immunology , Infertility, Female/pathology , Mice , Ovarian Cysts/complications , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation
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