Nat Rev Nephrol:促炎症消退脂质介质有望成为慢性肾病治疗的新药研究靶点

2021-08-01 MedSci原创 MedSci原创

肥胖、糖尿病、高血压和心血管疾病是慢性肾脏疾病(CKD)和肾衰竭的危险因素。

肥胖、糖尿病、高血压和血管疾病是慢性肾脏疾病(CKD)和肾衰竭的危险因素。慢性、轻度炎症被认为是CKD与肥胖、糖耐量受损、胰岛素抵抗和糖尿病之间的主要致病机制。因此,以炎症为靶点的CKD治疗策略引起了人们极大的兴趣。

对损伤或代谢功能障碍的炎症反应的初始阶段反映了促炎介质的释放,包括多肽、脂质和细胞因子,以及白细胞的招募。有研究指出,内源性脂质介质的发现,特别是前分解脂质介质和羟基脂肪酸的分支脂肪酸酯能促进炎症的消退,并减轻肥胖和糖尿病的微血管及大血管并发症,为治疗提供了潜在的新机会这篇综述将对此进行大致介绍。

要点:

  1. 炎症在糖尿病和肥胖相关肾病发病机制中的作用越来越受到重视,细胞因子和促炎脂质作为炎症的驱动因素在糖耐量受损、胰岛素抵抗和糖尿病的发病机制具有重要作用。
  2. 炎症的开始和消退是通过协调的宿主反应发生的,包括促炎和抗炎或促分解介质,这些介质以一种暂时可控的方式在器官损伤部位产生。
  3. 内源性脂质介质可促进炎症的消退,减轻糖尿病和肥胖的微血管和大血管并发症,这突出了治疗干预的潜在机会。
  4. 分解药理学是一种新的治疗方式,旨在有针对性地利用内源性促分解介质治疗慢性炎症,如糖尿病肾病。

脂肪组织通过脂肪-肾轴与肾脏的相互作用对正常肾功能以及对代谢损伤的反应都很重要(图1)。在代谢性疾病中,脂肪肥大、M1巨噬细胞积聚以及由此产生的胰岛素抵抗导致脂肪因子功能障碍和血脂异常。

升高的血浆甘油三酯、脂肪酸和低密度脂蛋白胆固醇可通过促进脂肪毒性、胰岛素抵抗和促炎症途径(称为肥胖相关肾小球疾病(ORG))而诱发肾功能障碍。在肾脏中,所有主要细胞类型的脂质异位积聚,导致系膜细胞、足细胞和近端小管细胞的结构和功能改变,最终引发肾脏疾病及肾衰。

图1.CKD的脂肾轴

专门的促分解脂质介质(SPMs)是在组织损伤部位通过内皮细胞和/或上皮细胞、浸润多形核细胞(PMN)之间的相互作用合成的。SPMs通过与表达在组织细胞和PMN上的特异性前分解G蛋白偶联受体结合来发挥作用。

促分解SPM生物作用包括抑制内皮细胞活化、阻断中性粒细胞外渗、促进非炎性单核细胞募集、促进an(M2)分解巨噬细胞表型、刺激中性粒细胞凋亡和巨噬细胞效应细胞增生。SPM由干细胞产生并作用于干细胞,有证据表明SPM介导这些细胞的免疫调节和抗炎作用。

促分解脂质介质在炎症消退中的作用

从治疗的角度来看,利用内源性SPMs的方法的一个主要限制是它们的相对不稳定性,但这可以通过人工模拟物的设计来避免。脂质体可以减弱实验性DKD的发展并逆转已确定的肾脏和大血管疾病,从药效学疗效的角度证明了原理。

此外,现有的治疗方法能在多大程度上调节糖尿病和肥胖的炎症仍不清楚,未来面临的挑战是确定糖尿病患者中这些脂类的产生是否存在缺陷。随着对促分解脂质的内源性产生途径理解的提高,有望开发出针对这些途径的新的治疗策略,以缓解糖尿病和肥胖症患者的肾脏疾病。

参考文献:Brennan, E., Kantharidis, P., Cooper, M.E. et al. Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function. Nat Rev Nephrol (2021). https://doi.org/10.1038/s41581-021-00454-y

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  1. [GetPortalCommentsPageByObjectIdResponse(id=1690070, encodeId=f6e716900e0c9, content=<a href='/topic/show?id=fb802e08724' target=_blank style='color:#2F92EE;'>#促炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=27087, encryptionId=fb802e08724, topicName=促炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1b3128951451, createdName=ms6127405442416114, createdTime=Sun Jan 23 18:00:18 CST 2022, time=2022-01-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1885343, encodeId=65fc188534351, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Oct 29 15:00:18 CST 2021, time=2021-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1198855, encodeId=e34d119885584, content=应该较促炎症消退,不叫促分解吧 , beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=/v1.0.0/img/user_icon.png, createdBy=78ac5580996, createdName=silly_mood, createdTime=Wed Mar 02 21:04:25 CST 2022, time=2022-03-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1004496, encodeId=20cd1004496ad, content=好文章,共享之。, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJlfgys76DEiaNtbYo2re3ibjrUPTRibEXRyFwAB4aAGiave842S0FQDf0wAoaH226NiaSoPPDzhndsf1g/132, createdBy=88b489038, createdName=yangchou, createdTime=Sun Aug 01 23:00:54 CST 2021, time=2021-08-01, status=1, ipAttribution=)]
  2. [GetPortalCommentsPageByObjectIdResponse(id=1690070, encodeId=f6e716900e0c9, content=<a href='/topic/show?id=fb802e08724' target=_blank style='color:#2F92EE;'>#促炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=27087, encryptionId=fb802e08724, topicName=促炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1b3128951451, createdName=ms6127405442416114, createdTime=Sun Jan 23 18:00:18 CST 2022, time=2022-01-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1885343, encodeId=65fc188534351, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Oct 29 15:00:18 CST 2021, time=2021-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1198855, encodeId=e34d119885584, content=应该较促炎症消退,不叫促分解吧 , beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=/v1.0.0/img/user_icon.png, createdBy=78ac5580996, createdName=silly_mood, createdTime=Wed Mar 02 21:04:25 CST 2022, time=2022-03-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1004496, encodeId=20cd1004496ad, content=好文章,共享之。, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJlfgys76DEiaNtbYo2re3ibjrUPTRibEXRyFwAB4aAGiave842S0FQDf0wAoaH226NiaSoPPDzhndsf1g/132, createdBy=88b489038, createdName=yangchou, createdTime=Sun Aug 01 23:00:54 CST 2021, time=2021-08-01, status=1, ipAttribution=)]
    2021-10-29 liye789132251
  3. [GetPortalCommentsPageByObjectIdResponse(id=1690070, encodeId=f6e716900e0c9, content=<a href='/topic/show?id=fb802e08724' target=_blank style='color:#2F92EE;'>#促炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=27087, encryptionId=fb802e08724, topicName=促炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1b3128951451, createdName=ms6127405442416114, createdTime=Sun Jan 23 18:00:18 CST 2022, time=2022-01-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1885343, encodeId=65fc188534351, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Oct 29 15:00:18 CST 2021, time=2021-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1198855, encodeId=e34d119885584, content=应该较促炎症消退,不叫促分解吧 , beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=/v1.0.0/img/user_icon.png, createdBy=78ac5580996, createdName=silly_mood, createdTime=Wed Mar 02 21:04:25 CST 2022, time=2022-03-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1004496, encodeId=20cd1004496ad, content=好文章,共享之。, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJlfgys76DEiaNtbYo2re3ibjrUPTRibEXRyFwAB4aAGiave842S0FQDf0wAoaH226NiaSoPPDzhndsf1g/132, createdBy=88b489038, createdName=yangchou, createdTime=Sun Aug 01 23:00:54 CST 2021, time=2021-08-01, status=1, ipAttribution=)]
    2022-03-02 silly_mood

    应该较促炎症消退,不叫促分解吧

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1690070, encodeId=f6e716900e0c9, content=<a href='/topic/show?id=fb802e08724' target=_blank style='color:#2F92EE;'>#促炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=27087, encryptionId=fb802e08724, topicName=促炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1b3128951451, createdName=ms6127405442416114, createdTime=Sun Jan 23 18:00:18 CST 2022, time=2022-01-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1885343, encodeId=65fc188534351, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Oct 29 15:00:18 CST 2021, time=2021-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1198855, encodeId=e34d119885584, content=应该较促炎症消退,不叫促分解吧 , beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=/v1.0.0/img/user_icon.png, createdBy=78ac5580996, createdName=silly_mood, createdTime=Wed Mar 02 21:04:25 CST 2022, time=2022-03-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1004496, encodeId=20cd1004496ad, content=好文章,共享之。, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJlfgys76DEiaNtbYo2re3ibjrUPTRibEXRyFwAB4aAGiave842S0FQDf0wAoaH226NiaSoPPDzhndsf1g/132, createdBy=88b489038, createdName=yangchou, createdTime=Sun Aug 01 23:00:54 CST 2021, time=2021-08-01, status=1, ipAttribution=)]
    2021-08-01 yangchou

    好文章,共享之。

    0

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