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Original Article

Korean J Physiol Pharmacol 2023; 27(3): 257-265

Published online May 1, 2023

Copyright © Korean J Physiol Pharmacol.

Rac1 inhibition protects the kidney against kidney ischemia/reperfusion through the inhibition of macrophage migration

You Ri Park1, Min Jung Kong2, Mi Ra Noh1, and Kwon Moo Park1,2,3,*

1Department of Biomedical Science and BK21 Plus, The Graduate School of Kyungpook National University, Daegu 41944, 2Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, 3Department of Anatomy, School of Medicine, Kyungpook National University, Daegu 41944, Korea

Correspondence to:Kwon Moo Park

Author contributions: Y.R.P., M.J.K., and M.R.N. performed the experiments and analyzed data. Y.R.P., M.R.N., and K.M.P. conceived the idea, designed the experiments, analyzed the data, and wrote the manuscript.

Received: February 14, 2023; Revised: March 13, 2023; Accepted: March 23, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


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: Acute kidney injury, Ischemia, Macrophages, Macrophage migration, Rac1-GTPase