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Gremlin1 and TGF-β1 protect kidney tubular epithelial cells from ischemia–reperfusion injury through different pathways

  • Nephrology - Original Paper
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Abstract

Background

Gremlin1 belongs to the superfamily members of transforming growth factor (TGF)-β1, playing a profibrotic role in chronic kidney diseases (CKD) and the transition from the late stage of acute kidney injury (AKI) to CKD, but the effect it plays in the early stage of AKI is unclear. This study aimed to investigate the role of Gremlin1on apoptosis in renal tubular epithelial cells under ischemia–reperfusion (I/R) induction.

Methods

We detected Gremlin1 and TGF-β1 expression in the kidneys of mice undergoing renal ischemia–reperfusion injury bilaterally. We induced apoptosis through depletion and reperfusion of oxygen and serum in human kidney tubular epithelial cells (HKCs), mimicking I/R injury in vivo, and detected the role and pathways of Gremlin1 and TGF-β1on HKCs injury.

Results

Mice undergoing bilateral I/R surgery presented AKI with a significant increase in serum creatinine, obvious renal tubular injuries, and increased macrophage cell and T-cell infiltration in interstitial areas. Gremlin1 expression was significantly increased along with TGF-β1 in the kidneys of AKI mice compared to sham mice. Exogenous Gremlin1 inhibited I/R-induced caspase3 expression in HKCs, which was blocked by a VEGFR2 kinase inhibitor III (SU5416). TGF-β1 also inhibited I/R-induced cell apoptosis in HKCs but had no synergic effect with Gremlin1. The TGF-β1’s inhibitory effect could be blocked by the TGF-β1 type I receptor (activin receptor-like kinase 5, and ALK5)-specific inhibitor SB431542.

Conclusions

Gremlin1 and TGF- β1 protect kidney tubular epithelial cells from ischemia–reperfusion-induced apoptosis through VEGFR2 and Smad2 signaling pathways.

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Acknowledgements

The authors would like to thank Wei Cui, Sa Liu, and Limin Zhao at the Beijing Institute of Heart, Lung and Blood Vessel Diseases for technical support.

Funding

This work was supported by a grant from Beijing Municipal Natural Science Foundation (7162055).

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Authors and Affiliations

  1. Department of General Internal Medicine, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen Road, Chao Yang District, Beijing, 100029, People’s Republic of China

    Xuxia Gao & Liping Ma

  2. Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Liyuan Han

  3. Department of Pharmaceutical Affairs, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Xinbao Yao

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  1. Xuxia Gao
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  2. Liyuan Han
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  3. Xinbao Yao
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Contributions

XG: experimental design, data generation and interpretation, manuscript draft, revision, approval, and submission. LH: experimental design, data generation, and interpretation. XY: experimental design, data generation, and interpretation. LM: experimental design, data interpretation, manuscript revision, and approval.

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Correspondence to Xuxia Gao or Liping Ma.

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Gao, X., Han, L., Yao, X. et al. Gremlin1 and TGF-β1 protect kidney tubular epithelial cells from ischemia–reperfusion injury through different pathways. Int Urol Nephrol 54, 1311–1321 (2022). https://doi.org/10.1007/s11255-021-03010-6

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  • DOI: https://doi.org/10.1007/s11255-021-03010-6

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