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Targeted VEGFA therapy in regulating early acute kidney injury and late fibrosis

Acta Pharmacologica Sinica volume 44, pages 1815–1825 (2023)Cite this article

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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Fig. 1: Incomplete recovery after 28 min of renal unilateral IRI.
Fig. 2: Comprehensive expression and localization of extraglomerular VEGFA in the progressive AKI.
Fig. 3: Correlation analysis of microvascular density, VEGFA expression, and renal fibrosis in the AKI process.
Fig. 4: Early exogenous VEGFA therapy protects against AKI by preserving renal microvessel structure and counteracting secondary hypoxic insults.
Fig. 5: Late anti-VEGFA treatment attenuates renal fibrosis progression.
Fig. 6: Proteomic analysis for the molecular mechanism of renal fibrosis alleviation by anti-VEGFA.
Fig. 7: Schematic illustration depicting the dual role of VEGFA in regulating early acute kidney injury and late fibrosis.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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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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  1. These authors contributed equally: Meng-jie Huang, Yu-wei Ji, Jian-wen Chen

Authors and Affiliations

  1. Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China

    Meng-jie Huang, Yu-wei Ji, Jian-wen Chen, Xu Wang, Xiao-fan Li, Yi-fan Zhang, Xiang Yu, Ling-ling Wu, Xue-feng Sun, Guang-yan Cai, Xiang-mei Chen, Quan Hong & Zhe Feng

  2. Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, 300072, China

    Duo Li

  3. The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, China

    Tian Zhou

  4. Department of Emergency, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China

    Peng Qi

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Contributions

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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Correspondence to Quan Hong or Zhe Feng.

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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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