caa a22 4500 606174796 CHVBK 20210128100739.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s00018-015-1888-0 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1888-0 Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome [Elektronische Daten] [I-Jung Tsai, Chia-Hung Chou, Yao-Hsu Yang, Wei-Chou Lin, Yen-Hung Lin, Lu-Ping Chow, Hsiao-Hui Lee, Pei-Gang Kao, Wan-Ting Liau, Tzuu-Shuh Jou, Yong-Kwei Tsau] 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. Springer Basel, 2015 Minimal change disease nationallicence ROCK nationallicence Adherens junction nationallicence VE-cadherin nationallicence Actin stress fiber nationallicence Tsai I-Jung Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut Chou Chia-Hung Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut Yang Yao-Hsu Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut Lin Wei-Chou Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut Lin Yen-Hung Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut Chow Lu-Ping Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan aut Lee Hsiao-Hui Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan aut Kao Pei-Gang Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan aut Liau Wan-Ting Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut Jou Tzuu-Shuh Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut Tsau Yong-Kwei Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut Cellular and Molecular Life Sciences Springer Basel 72/16(2015-08-01), 3157-3171 1420-682X 72:16<3157 2015 72 18 https://doi.org/10.1007/s00018-015-1888-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1888-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tsai I-Jung Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chou Chia-Hung Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Yang Yao-Hsu Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Lin Wei-Chou Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Lin Yen-Hung Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chow Lu-Ping Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Lee Hsiao-Hui Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Kao Pei-Gang Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Liau Wan-Ting Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Jou Tzuu-Shuh Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 700 1- Tsau Yong-Kwei Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/16(2015-08-01), 3157-3171 1420-682X 72:16<3157 2015 72 18