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  • Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome.

Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome.

Cellular and molecular life sciences : CMLS (2015-03-21)
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
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.

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