Lee Yashang, Blount Katrina Lehmann, Dai Feng, Thompson Siobhan, Scher Jonathan Kaufman, Bitterman Sherrie, Droher Madeline, Herzog Erica L, Moeckel Gilbert, Karihaloo Anil, Dahl Neera K
Section of Nephrology, Yale University School of Medicine, New Haven, CT, 06510, USA.
Department of Biostatics, Yale University School of Public Health, 300 George Street, New Haven, CT, 06511, USA.
Clin Exp Nephrol. 2018 Aug;22(4):906-916. doi: 10.1007/s10157-018-1542-x. Epub 2018 Feb 16.
Semaphorin 7A (SEMA7A) is an immunomodulating protein implicated in lung and liver fibrosis. In autosomal-dominant polycystic kidney disease (ADPKD), the progressive expansion of renal cysts, inflammation, and subsequent renal fibrosis leads to end-stage renal disease (ESRD). SEMA7A may play a role in renal fibrosis and in ADPKD.
We evaluated Sema7a in a mouse model of renal fibrosis and determined the expression of SEMA7A in human ADPKD kidney. We analyzed SEMA7A expression on peripheral blood mononuclear cells (PBMCs), including CD45 (leukocyte), CD14(monocyte), CD4+ (T lymphocytes) and CD4Foxp3CD25 [regulatory T lymphocytes (Tregs)] from 90 ADPKD patients (11 tolvaptan treated and 79 tolvaptan naïve), and 21 healthy volunteers, using a Fluorescence-Activated Cell Sorting (FACS).
Sema7a is required for renal fibrosis. SEMA7A shows robust expression in ADPKD kidneys, localizing to cysts derived from distal tubules. SEMA7A is higher in circulating monocytes, but unchanged in CD4 lymphocytes in ADPKD patients. The SEMA7A increase was detected early (stage 1 CKD) and seemed more prominent in patients with smaller kidneys (p = 0.09). Compared to tolvaptan-naïve ADPKD patients, those treated with tolvaptan showed reduced SEMA7A expression on monocytes, T lymphocytes, and Tregs, although the number of PBMCs was unchanged. After 1 month of tolvaptan treatment, SEMA7A expression on Tregs decreased.
SEMA7A shows potential as both a therapeutic target in mammalian kidney fibrosis and as a marker of inflammation in ADPKD patients. SEMA7A expression was lower after tolvaptan treatment, which may reflect drug efficacy.
信号素7A（SEMA7A）是一种参与肺和肝纤维化的免疫调节蛋白。在常染色体显性多囊肾病（ADPKD）中，肾囊肿的渐进性扩张、炎症以及随后的肾纤维化会导致终末期肾病（ESRD）。SEMA7A可能在肾纤维化和ADPKD中发挥作用。
我们在肾纤维化小鼠模型中评估了Sema7a，并确定了SEMA7A在人类ADPKD肾脏中的表达。我们使用荧光激活细胞分选（FACS）分析了90例ADPKD患者（11例接受托伐普坦治疗，79例未接受托伐普坦治疗）和21名健康志愿者外周血单个核细胞（PBMC）上SEMA7A的表达，这些细胞包括CD45（白细胞）、CD14（单核细胞）、CD4 +（T淋巴细胞）和CD4Foxp3CD25 [调节性T淋巴细胞（Tregs）]。
肾纤维化需要Sema7a。SEMA7A在ADPKD肾脏中表达强烈，定位于源自远端小管的囊肿。ADPKD患者循环单核细胞中的SEMA7A较高，但CD4淋巴细胞中的SEMA7A无变化。SEMA7A的增加在早期（慢性肾脏病1期）即可检测到，并且在肾脏较小的患者中似乎更为明显（p = 0.09）。与未接受托伐普坦治疗的ADPKD患者相比，接受托伐普坦治疗的患者单核细胞、T淋巴细胞和Tregs上的SEMA7A表达降低，尽管PBMC的数量未变。托伐普坦治疗1个月后，Tregs上的SEMA7A表达降低。
SEMA7A显示出作为哺乳动物肾纤维化治疗靶点以及ADPKD患者炎症标志物的潜力。托伐普坦治疗后SEMA7A表达降低，这可能反映了药物疗效。
