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

Abstract

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.

SerpinA3K Deficiency Reduces Oxidative Stress in Acute Kidney Injury

“…Consistent with the fact that Vegfa, a gene target of β-catenin and HIF-1α, is downregulated when SerpinA3K is overexpressed, in this study, we observed the opposite effect in the KOSA3+IR group [14,15,17,19]. Furthermore, it is known that the early activation of HIF-1α and the overexpression of VEGFA may promote repair after an AKI episode [23,32]. These findings suggest that SerpinA3K regulation of Vegfa during AKI is not only through the Wnt-β-catenin pathway.…”

Bi-functional KIT-PR1P peptides combine with VEGF to protect ischemic kidney in rats by targeting to Kim-1

“…VEGF was reported to protect kidney cells against hypoxic injury after renal ischemia [ 4 ].TUNEL staining was used to determine the number of apoptotic cells after renal I/R injury ( Fig. 6 A–F).…”

“…After ischemic injury of kidney, VEGF could induce angiogenesis by promoting endothelial cells proliferation and also protect renal cells from I/R injury. Thus, it was reported to improve the renal function and inhibit tissue fibrosis of further development of AKI [ 4 ]. At present, the administration of VEGF after AKI often utilized intraperitoneal, intravenous or subcutaneous intrarenal injection.…”

Gut Microbiota and Neonatal Acute Kidney Injury

“…29 After AKI, epidermal growth factor promotes VEGF secretion, which in turn facilitates the proliferation of endothelial cells of peritubular capillaries, thereby improving tubular injury. 30,31 It was found that VEGF attenuates renal capillary injury and fibrosis and improves tubular injury and renal function in rodent AKI caused by ischemia-reperfusion. 32,33 Furthermore, VEGF enhanced the protective effects of human amniotic fluid stem cells in a rat model of renal ischemia-reperfusion and potentiated the beneficial effect of erythropoietin on sepsis-induced AKI in mice.…”