The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Rac1 inhibition protects the kidney against kidney ischemia/reperfusion through the inhibition of macrophage migration

  • You Ri Park (Department of Biomedical Science and BK21 Plus, The Graduate School of Kyungpook National University) ;
  • Min Jung Kong (Cardiovascular Research Institute, Kyungpook National University) ;
  • Mi Ra Noh (Department of Biomedical Science and BK21 Plus, The Graduate School of Kyungpook National University) ;
  • Kwon Moo Park (Department of Biomedical Science and BK21 Plus, The Graduate School of Kyungpook National University)
  • Received : 2023.02.14
  • Accepted : 2023.03.23
  • Published : 2023.05.01
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Abstract

Kidney ischemia/reperfusion (I/R) injury, a common cause of acute kidney injury (AKI), is associated with the migration of inflammatory cells into the kidney. Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho family of small GTPase, plays an important role in inflammatory cell migration by cytoskeleton rearrangement. Here, we investigated the role of Rac1 on kidney I/R injury and macrophage migration. Male mice were subjected to either 25 min of bilateral ischemia followed by reperfusion (I/R) or a sham operation. Some mice were administrated with either NSC23766, an inhibitor of Rac1, or 0.9% NaCl (vehicle). Kidney damage and Rac1 activity and expression were measured. The migration and lamellipodia formation of RAW264.7 cells, mouse monocyte/macrophage, induced by monocyte chemoattractant protein-1 (MCP-1, a chemokine) were determined using transwell migration assay and phalloidin staining, respectively. In sham-operated kidneys, Rac1 was expressed in tubular cells and interstitial cells. In I/R-injured kidneys, Rac1 expression was decreased in tubule cells in correlation with the damage of tubular cells, whereas Rac1 expression increased in the interstitium in correlation with an increased population of F4/80 cells, monocytes/macrophages. I/R increased Rac1 activity without changing total Rac1 expression in the whole kidney lysates. NSC23766 administration blocked Rac1 activation and protected the kidney against I/R-induced kidney damage and interstitial F4/80 cell increase. NSC23766 suppressed monocyte MCP-1-induced lamellipodia and filopodia formation and migration of RAW 264.7 cells. These results indicate Rac1 inhibition protects the kidney against I/R via inhibition of monocytes/macrophages migration into the kidney.

Keywords

Acknowledgement

This study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (MIST) (NRF 2020R1A2C2006903) and a grant from the Korea Health Technology R&D Project (HI15C0001) through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Korea government.

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