Janus kinase 2/signal transducer and activator of transcription 3 inhibitors attenuate the effect of cardiotrophin-like cytokine factor 1 and human focal segmental glomerulosclerosis serum on glomerular filtration barrier.
Janus kinase 2/signal transducer and activator of transcription 3 inhibitors attenuate the effect of cardiotrophin-like cytokine factor 1 and human focal segmental glomerulosclerosis serum on glomerular filtration barrier.
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DOI：
10.1016/j.trsl.2015.03.002
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Savin VJ
中科院分区：
文献类型：
--
作者：
Sharma M;Zhou J;Gauchat JF;Sharma R;McCarthy ET;Srivastava T;Savin VJ
Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) after renal transplantation is believed to be caused by a circulating factor(s). We detected cardiotrophin-like cytokine 1 (CLCF1), a member of the IL-6 family, in the plasma from patients with recurrent FSGS. We hypothesized that CLCF1 contributes to the effect of FSGS serum on the glomerular filtration barrier in vitro. Presently, we studied the effect of CLCF1 on isolated rat glomeruli using an in vitro assay of albumin permeability (Palb). CLCF1 (0.05–100 ng/mL) increased Palb and caused maximal effect at 5–10 ng/mL (P<0.001). The increase in Palb was analogous to the effect of FSGS serum. Anti-CLCF1 monoclonal antibody blocked the CLCF1-induced increase in Palb and significantly attenuated the effect of FSGS serum (P<0.001). The heterodimer composed of CLCF1 and co-secreted molecule cytokine receptor-like factor-1 (CRLF1) attenuated the increase in Palb caused by CLCF1 or FSGS serum. Western blot analysis showed that CLCF1 upregulated phosphorylation of STAT3 (Tyr705) in glomeruli. This effect was diminished by the heterodimer CLCF1-CRLF1. JAK2 inhibitor BMS-1119543 or STAT3 inhibitor Stattic significantly blocked the effect of CLCF1 or FSGS serum on Palb (P<0.001). These novel findings suggest that while monomeric CLCF1 increases Palb, the heterodimer CLCF1-CRLF1 may protect the glomerular filtration barrier. We speculate that albuminuria in FSGS is related to qualitative or quantitative changes in the CLCF1-CRLF1 complex and, that JAK2 or STAT3 inhibitors may be novel therapeutic agents to treat FSGS.
