Sharma Mukut, Zhou Jianping, Gauchat Jean-François, Sharma Ram, McCarthy Ellen T, Srivastava Tarak, Savin Virginia J
Renal Research Laboratory, Research and Development, MBRF and Kansas City VA Medical Center, Kansas City, Mo; Kidney Institute, University of Kansas Medical Center, Kansas City, Kan.
Renal Research Laboratory, Research and Development, MBRF and Kansas City VA Medical Center, Kansas City, Mo.
Transl Res. 2015 Oct;166(4):384-98. doi: 10.1016/j.trsl.2015.03.002. Epub 2015 Mar 16.
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 factor 1 (CLCF1), a member of the interleukin 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 (P(alb)). CLCF1 (0.05-100 ng/mL) increased P(alb) 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 P(alb) and significantly attenuated the effect of FSGS serum (P < 0.001). The heterodimer composed of CLCF1 and cosecreted molecule cytokine receptor-like factor 1 (CRLF1) attenuated the increase in P(alb) caused by CLCF1 or FSGS serum. Western blot analysis showed that CLCF1 upregulated phosphorylation of signal transducer and activator of transcription 3 (STAT3) (Tyr705) in glomeruli. This effect was diminished by the heterodimer CLCF1-CRLF1. Janus kinase 2 (JAK2) inhibitor BMS-1119543 or STAT3 inhibitor Stattic significantly blocked the effect of CLCF1 or FSGS serum on P(alb) (P < 0.001). These novel findings suggest that when monomeric CLCF1 increases P(alb), 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.
肾移植后特发性局灶节段性肾小球硬化（FSGS）复发被认为是由循环因子引起的。我们在复发型FSGS患者的血浆中检测到了白细胞介素6家族成员心肌营养素样细胞因子1（CLCF1）。我们推测CLCF1在体外对FSGS血清影响肾小球滤过屏障起作用。目前，我们使用白蛋白通透性（P(alb)）体外测定法研究了CLCF1对分离的大鼠肾小球的影响。CLCF1（0.05 - 100 ng/mL）可增加P(alb)，并在5 - 10 ng/mL时产生最大效应（P < 0.001）。Palb的增加类似于FSGS血清的作用。抗CLCF1单克隆抗体可阻断CLCF1诱导的P(alb)增加，并显著减弱FSGS血清的作用（P < 0.001）。由CLCF1和共分泌分子细胞因子受体样因子1（CRLF1）组成的异二聚体可减弱CLCF1或FSGS血清引起的P(alb)增加。蛋白质印迹分析表明，CLCF1可上调肾小球中信号转导子和转录激活子3（STAT3）（Tyr705）的磷酸化。这种效应被异二聚体CLCF1 - CRLF1减弱。Janus激酶2（JAK2）抑制剂BMS - 1119543或STAT3抑制剂Stattic可显著阻断CLCF1或FSGS血清对P(alb)的作用（P < 0.001）。这些新发现表明，当单体CLCF1增加P(alb)时，异二聚体CLCF1 - CRLF1可能保护肾小球滤过屏障。我们推测FSGS中的蛋白尿与CLCF1 - CRLF1复合物的质量或数量变化有关，并且JAK2或STAT3抑制剂可能是治疗FSGS的新型治疗药物。
