Tubular epithelial cells-derived small extracellular vesicle-VEGF-A promotes peritubular capillary repair in ischemic kidney injury

npj Regenerative Medicine

Article

Yi Wen¹  Cui Wang¹  Xiao-Xiao Zhu¹  An-Ran Shen¹  Jing-Yuan Cao¹  Xin Zhong¹  Bin Wang¹  Bi-Cheng Liu¹  Tao-Tao Tang¹  Jing Jing¹  Zuo-Lin Li¹  Lin-Li Lv¹  Suo-Fu Qin² 

[1] Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, 87 Ding Jia Qiao Road, Nanjing, China;Kexing Biopharm Co., Ltd, Floor 15-19, Building B, Chuangyi Technology Building, No. 198, Keji Middle 1st Road, Nanshan, Shenzhen, China;

DOI  :  10.1038/s41536-022-00268-x

 received in 2022-04-16, accepted in 2022-11-30,  发布年份 2022

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2022

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