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既往研究提示，高濃度葡萄糖是誘導(dǎo)糖尿病腎病纖維化的主要病理機(jī)制。高濃度的葡萄糖可誘導(dǎo)腎小管導(dǎo)管上皮細(xì)胞α-SMA表達(dá)[4-5]，α-SMA為肌成纖維細(xì)胞的標(biāo)志性蛋白，是反映上皮細(xì)胞轉(zhuǎn)分化主要觀察指標(biāo)。目前發(fā)現(xiàn)，高糖促轉(zhuǎn)分化的作用機(jī)制主要是通過上調(diào)各種細(xì)胞分化或基質(zhì)增殖的蛋白水平，例如TGF-β1、PTHrP、Ⅰ型膠原及MMP-2等，TGF-β1、PTHrP信號(hào)通路在器官纖維化中的作用已經(jīng)明確，其水平升高可以通過上調(diào)Smad系列蛋白表達(dá)，誘導(dǎo)細(xì)胞轉(zhuǎn)分化為纖維細(xì)胞。而Ⅰ型膠原及MMP-2是參與基質(zhì)沉積及積聚的主要調(diào)控蛋白，同時(shí)以自分泌及旁分泌方式作用本體細(xì)胞或鄰近細(xì)胞，從而放大纖維化效應(yīng)[4-7]。其他細(xì)胞包括血管內(nèi)皮細(xì)胞、平滑肌細(xì)胞等不僅是單純性高糖，間歇性高糖同樣可以從多個(gè)水平影響細(xì)胞分化通路TGFβ1/Smad信號(hào)轉(zhuǎn)導(dǎo)，從而加重纖維化進(jìn)程[2-3]。
本研究發(fā)現(xiàn)，高濃度葡萄糖環(huán)境或間歇性高糖分別作用NRK-52EA細(xì)胞后，其TGF-β1、Ⅰ型膠原、MMP-2、α-SMA以及PTHrP表達(dá)水平均顯著上調(diào);間歇性高糖TGF-β1、MMP2以及α-SMA表達(dá)較持續(xù)性高糖作用更為顯著，該結(jié)果與Polhill等[8]對(duì)腎小球系膜細(xì)胞研究結(jié)果—間歇性高糖可以促進(jìn)腎小球系膜細(xì)胞纖維化相似，故推測(cè)間歇性高糖較持續(xù)性高糖可能更容易通過激活TGF-β1、MMP-2而誘導(dǎo)腎小管導(dǎo)管上皮細(xì)胞NRK-52EA轉(zhuǎn)分化為含α-SMA的間充質(zhì)細(xì)胞，加重腎臟纖維化。
本研究結(jié)果還發(fā)現(xiàn)，間歇性高糖能顯著上調(diào)NRK-52EA細(xì)胞株的ROS含量，其水平高于單純性高糖組。Quagliaro等[9]研究提示間歇性高糖能通過氧化應(yīng)激作用促進(jìn)ROS積聚，誘導(dǎo)各種炎癥因子包括MMP等表達(dá)，而該系列炎癥因子已經(jīng)被證實(shí)參與誘導(dǎo)腎小管導(dǎo)管上皮轉(zhuǎn)分化為間充質(zhì)細(xì)胞進(jìn)程[10]，Jones等[11]也發(fā)現(xiàn)間歇性高糖能顯著誘導(dǎo)人臍靜脈內(nèi)皮細(xì)胞氧化應(yīng)激反應(yīng)標(biāo)記物硝基酪氨酸含量升高，從而促進(jìn)細(xì)胞凋亡。故認(rèn)為間歇性高糖誘導(dǎo)NRK-52EA細(xì)胞轉(zhuǎn)分化作用比持續(xù)性高糖更顯著，其機(jī)制可能是間歇性高糖誘導(dǎo)細(xì)胞內(nèi)氧化應(yīng)激更嚴(yán)重，從而促進(jìn)腎小管導(dǎo)管上皮細(xì)胞TGF-β1、MMP-2等系列蛋白的表達(dá)以拮抗炎癥反應(yīng)，而TGF-β1、MMP-2蛋白表達(dá)上調(diào)，又進(jìn)一步加重腎小管上皮細(xì)胞纖維化進(jìn)程。
綜上所述，間歇性高糖對(duì)腎小管上皮細(xì)胞的損害應(yīng)該更予重視。提示臨床控制血糖平穩(wěn)是糖尿病治療的重要基礎(chǔ)，在此基礎(chǔ)上適當(dāng)抗氧化治療有望減輕氧化應(yīng)激, 保護(hù)腎小管上皮細(xì)胞, 遲滯其轉(zhuǎn)分化, 可能會(huì)延緩糖尿病并發(fā)癥的發(fā)展醫(yī).學(xué).全.在.線gydjdsj.org.cn。
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