title: Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome.
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.
authors: Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors: I-Jung
authors: IJ
authors: Tsai
authors: Chia-Hung
authors: CH
authors: Chou
authors: Yao-Hsu
authors: YH
authors: Yang
authors: Wei-Chou
authors: WC
authors: Lin
authors: Yen-Hung
authors: YH
authors: Lin
authors: Lu-Ping
authors: LP
authors: Chow
authors: Hsiao-Hui
authors: HH
authors: Lee
authors: Pei-Gang
authors: PG
authors: Kao
authors: Wan-Ting
authors: WT
authors: Liau
authors: Tzuu-Shuh
authors: TS
authors: Jou
authors: Yong-Kwei
authors: YK
authors: Tsau
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002648:Child; D015936:Complement C5a / Q000009:adverse effects* / Q000378:metabolism; D016207:Cytokines / Q000032:analysis; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007124:Immunoenzyme Techniques; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D046529:Microscopy, Electron, Transmission; D009404:Nephrotic Syndrome / Q000150:complications*; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000009:adverse effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D016207:Cytokines; D017931:DNA Primers; D011725:Pyridines; D011994:Recombinant Proteins; C108830:Y 27632; D015936:Complement C5a; D054460:rho-Associated Kinases