Abstract
Damage to peritubular capillaries is a key process that contributes to acute kidney injury (AKI) progression. Vascular endothelial growth factor A (VEGFA) plays a critical role in maintaining the renal microvasculature. However, the physiological role of VEGFA in various AKI durations remains unclear. A severe unilateral ischemia‒reperfusion injury model was established to provide an overview of VEGFA expression and the peritubular microvascular density from acute to chronic injury in mouse kidneys. Therapeutic strategies involving early VEGFA supplementation protecting against acute injury and late anti-VEGFA treatment for fibrosis alleviation were analyzed. A proteomic analysis was conducted to determine the potential mechanism of renal fibrosis alleviation by anti-VEGFA. The results showed that two peaks of extraglomerular VEGFA expression were observed during AKI progression: one occurred at the early phase of AKI, and the other occurred during the transition to chronic kidney disease (CKD). Capillary rarefaction progressed despite the high expression of VEGFA at the CKD stage, and VEGFA was associated with interstitial fibrosis. Early VEGFA supplementation protected against renal injury by preserving microvessel structures and counteracting secondary tubular hypoxic insults, whereas late anti-VEGFA treatment attenuated renal fibrosis progression. The proteomic analysis highlighted an array of biological processes related to fibrosis alleviation by anti-VEGFA, which included regulation of supramolecular fiber organization, cell-matrix adhesion, fibroblast migration, and vasculogenesis. These findings establish the landscape of VEGFA expression and its dual roles during AKI progression, which provides the possibility for the orderly regulation of VEGFA to alleviate early acute injury and late fibrosis.
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Acknowledgements
This work was supported by Beijing Natural Science Foundation (7222169); National Natural Science Foundation of China (82000631, 82070741, 82030025, 82100713 and 32200579); Young Elite Scientist Sponsorship Program by CAST (YESS20200400); National Key Research and Development Project (2018YFE0126600); Young Talent Project of Chinese PLA General Hospital (20230404).
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MJH: experiments design, collection and assembly of data, data analysis and interpretation, and manuscript writing. YWJ: animal surgery, collection and assembly of data, data analysis and interpretation. JWC and LLW: data analysis and interpretation. DL, TZ, XFL, YFZ, and XY: conducting experiments. PQ and XW: performing all bioinformatics associated with this study. XFS, GYC and XMC: experiments design. ZF and QH: financial support, conception and design, manuscript revision, final approval of manuscript.
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Huang, Mj., Ji, Yw., Chen, Jw. et al. Targeted VEGFA therapy in regulating early acute kidney injury and late fibrosis. Acta Pharmacol Sin 44, 1815–1825 (2023). https://doi.org/10.1038/s41401-023-01070-1
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DOI: https://doi.org/10.1038/s41401-023-01070-1