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基质细胞衍生因子 1α（SDF-1α）可诱导心脏成纤维细胞、肾微血管平滑肌细胞和肾小球系膜细胞增殖、肥大，并产生胶原。

SDF-1α (Stromal Cell-Derived Factor 1α) Induces Cardiac Fibroblasts, Renal Microvascular Smooth Muscle Cells, and Glomerular Mesangial Cells to Proliferate, Cause Hypertrophy, and Produce Collagen.

机构信息

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

出版信息

J Am Heart Assoc. 2017 Nov 7;6(11):e007253. doi: 10.1161/JAHA.117.007253.

DOI:10.1161/JAHA.117.007253
PMID:29114002
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5721794/
Abstract

BACKGROUND

Activated cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), and glomerular mesangial cells (GMCs) proliferate, cause hypertrophy, and produce collagen; in this way, activated CFs contribute to cardiac fibrosis, and activated PGVSMCs and GMCs promote renal fibrosis. In heart and kidney diseases, SDF-1α (stromal cell-derived factor 1α; endogenous CXCR4 [C-X-C motif chemokine receptor 4] receptor agonist) levels are often elevated; therefore, it is important to know whether and how the SDF-1α/CXCR4 axis activates CFs, PGVSMCs, or GMCs.

METHODS AND RESULTS

Here we investigated whether SDF-1α activates CFs, PGVSMCs, and GMCs to proliferate, hypertrophy, or produce collagen. DPP4 (dipeptidyl peptidase 4) inactivates SDF-1α and previous experiments show that growth-promoting peptides have greater effects in cells from genetically-hypertensive animals. Therefore, we performed experiments in the absence and presence of sitagliptin (DPP4 inhibitor) and in cells from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats. Our studies show (1) that spontaneously hypertensive and Wistar-Kyoto rat CFs, PGVSMCs, and GMCs express CXCR4 receptors and DPP4 activity; (2) that chronic treatment with physiologically relevant concentrations of SDF-1α causes concentration-dependent increases in the proliferation (cell number) and hypertrophy (H-leucine incorporation) of and collagen production (H-proline incorporation) by CFs, PGVSMCs, and GMCs; (3) that sitagliptin augments these effects of SDF-1α; (4) that interactions between SDF-1α and sitagliptin are greater in spontaneously hypertensive rat cells; (5) that CXCR4 antagonism (AMD3100) blocks all effects of SDF-1α; and (6) that SDF-1α/CXCR4 signal transduction likely involves the RACK1 (receptor for activated C kinase 1)/Gβγ/PLC (phospholipase C)/PKC (protein kinase C) signaling complex.

CONCLUSIONS

The SDF-1α/CXCR4 axis drives proliferation and hypertrophy of and collagen production by CFs, PGVSMCs, and GMCs, particularly in cells from genetically hypertensive animals and when DPP4 is inhibited.

摘要

背景

激活的心肌成纤维细胞（CFs）、肾小球前血管平滑肌细胞（PGVSMCs）和肾小球系膜细胞（GMCs）增殖、肥大并产生胶原蛋白；由此，激活的 CFs 导致心肌纤维化，而激活的 PGVSMCs 和 GMCs 则促进肾纤维化。在心脏和肾脏疾病中，SDF-1α（基质细胞衍生因子 1α；内源性 CXCR4 [C-X-C 基序趋化因子受体 4] 受体激动剂）水平通常升高；因此，了解 SDF-1α/CXCR4 轴是否以及如何激活 CFs、PGVSMCs 或 GMCs 非常重要。

方法和结果

在这里，我们研究了 SDF-1α 是否激活 CFs、PGVSMCs 和 GMCs 以增殖、肥大或产生胶原蛋白。DPP4（二肽基肽酶 4）使 SDF-1α 失活，并且先前的实验表明，在遗传高血压动物的细胞中，促生长肽具有更大的作用。因此，我们在不存在和存在西他列汀（DPP4 抑制剂）的情况下以及在来自正常血压 Wistar-Kyoto 大鼠和自发性高血压大鼠的细胞中进行了实验。我们的研究表明：（1）自发性高血压和 Wistar-Kyoto 大鼠 CFs、PGVSMCs 和 GMCs 表达 CXCR4 受体和 DPP4 活性；（2）用生理相关浓度的 SDF-1α 慢性处理会导致 CFs、PGVSMCs 和 GMCs 的增殖（细胞数量）和肥大（H-亮氨酸掺入）以及胶原蛋白产生（H-脯氨酸掺入）呈浓度依赖性增加；（3）西他列汀增强了 SDF-1α 的这些作用；（4）SDF-1α 与西他列汀之间的相互作用在自发性高血压大鼠细胞中更大；（5）CXCR4 拮抗剂（AMD3100）阻断 SDF-1α 的所有作用；（6）SDF-1α/CXCR4 信号转导可能涉及 RACK1（激活的 C 激酶 1 受体）/Gβγ/PLC（磷脂酶 C）/PKC（蛋白激酶 C）信号复合物。

结论

SDF-1α/CXCR4 轴驱动 CFs、PGVSMCs 和 GMCs 的增殖、肥大和胶原蛋白产生，特别是在遗传高血压动物的细胞中，并且当 DPP4 被抑制时。

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