Tubular epithelial cells-derived small extracellular vesicle-VEGF-A promotes peritubular capillary repair in ischemic kidney injury.
Tubular epithelial cells-derived small extracellular vesicle-VEGF-A promotes peritubular capillary repair in ischemic kidney injury.
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DOI：
10.1038/s41536-022-00268-x
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发表时间：
2022-12-17
影响因子：
7.2
通讯作者：
Lv, Lin-Li
中科院分区：
文献类型：
--
作者：
Zhong, Xin;Tang, Tao-Tao;Shen, An-Ran;Cao, Jing-Yuan;Jing, Jing;Wang, Cui;Zhu, Xiao-Xiao;Wen, Yi;Li, Zuo-Lin;Wang, Bin;Qin, Suo-Fu;Liu, Bi-Cheng;Lv, Lin-Li
肾小管周围毛细血管（Peritubular capillary，PTC）与肾小管在结构和功能上密切相关，两者都是急性肾损伤（acute kidney injury，阿基）发生、发展的关键调节因子。然而，阿基期间PTC和肾小管之间相互作用的机制仍不清楚。在这里，我们探索了一种新的模式，小管血管串扰介导的小细胞外囊泡（sEV）后阿基。肾缺血再灌注（I/R）损伤后，肾小管上皮细胞增殖和血管内皮生长因子-A（VEGF-A）表达增加，并伴有VEGF-A胞浆向肾小管细胞基底侧的明显再分布。同时，VEGF-A的分泌模式在损伤的肾小管细胞中发生了转变，其显示出更大的倾向于通过sEV而不是游离形式分泌VEGF-A。有趣的是，肾小管细胞来源的VEGF-A-富集的sEV（sEV-VEGF-A）被证明促进内皮细胞增殖，其由VEGF受体1和2调节。此外，通过Rab 27 a敲低抑制肾sEV分泌导致体内小管周围内皮细胞增殖的显著降低。重要的是，利用新认识到的PTC的内源性修复反应，外源性补充VEGF-A + sEV有效地避免了PTC稀疏，改善了肾灌注，并阻止了阿基向CKD的转变。总之，我们的研究揭示了阿基后通过sEV-VEGF-A通过肾小管-PTC串扰的新型内在修复反应，这可以被用作缺血性疾病中有前途的治疗性血管生成策略。
Peritubular capillaries (PTCs) are closely related to renal tubules in structure and function, and both are pivotal regulators in the development and progression of acute kidney injury (AKI). However, the mechanisms that underlie the interaction between PTCs and tubules during AKI remain unclear. Here we explored a new mode of tubulovascular crosstalk mediated by small extracellular vesicles (sEV) after AKI. In response to renal ischemia/reperfusion (I/R) injury, endothelial proliferation of PTCs and tubular expression of vascular endothelial growth factor-A (VEGF-A) were increased, accompanied by a remarkable redistribution of cytoplasmic VEGF-A to the basolateral side of tubular cells. Meanwhile, the secretion mode of VEGF-A was converted in the injured tubular cells, which showed a much greater tendency to secrete VEGF-A via sEV other than the free form. Interestingly, tubular cell-derived VEGF-A-enriched sEV (sEV-VEGF-A) turned out to promote endothelial proliferation which was regulated by VEGF receptors 1 and 2. Furthermore, inhibition of renal sEV secretion by Rab27a knockdown resulted in a significant decrease in the proliferation of peritubular endothelial cells in vivo. Importantly, taking advantage of the newly recognized endogenous repair response of PTCs, exogenous supplementation of VEGF-A + sEV efficiently recused PTC rarefaction, improved renal perfusion, and halted the AKI to CKD transition. Taken together, our study uncovered a novel intrinsic repair response after AKI through renal tubule-PTC crosstalk via sEV-VEGF-A, which could be exploited as a promising therapeutic angiogenesis strategy in diseases with ischemia.
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影响因子：
41.5
作者：
Ferenbach, David A.;Bonventre, Joseph V.
通讯作者：
Bonventre, Joseph V.
DOI：
10.1186/cc11454
发表时间：
2013-02-04
期刊：
Critical care (London, England)
影响因子：
--
作者：
Kellum JA;Lameire N;KDIGO AKI Guideline Work Group
通讯作者：
KDIGO AKI Guideline Work Group
影响因子：
3.3
作者：
Guzmán-Hernández ML;Potter G;Egervári K;Kiss JZ;Balla T
通讯作者：
Balla T
影响因子：
13.6
作者：
Borges, Fernanda T.;Melo, Sonia A.;Kalluri, Raghu
通讯作者：
Kalluri, Raghu
影响因子：
13.6
作者：
Dominguez, Jesus H.;Liu, Yunlong;Kelly, K. J.
通讯作者：
Kelly, K. J.