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Am J Physiol Renal Physiol. 2016 Apr 1;310(7):F607-F620. doi: 10.1152/ajprenal.00169.2015. Epub 2015 Dec 23.

G protein α12 (Gα12) is a negative regulator of kidney injury molecule-1-mediated efferocytosis.

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Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.
Renal Division and Biomedical Engineering Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
Department of Microbiology and Immunology, Western University, London, Ontario, Canada;
Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.


Kidney injury molecule-1 (KIM-1) is a receptor for the "eat me" signal, phosphatidylserine, on apoptotic cells. The specific upregulation of KIM-1 by injured tubular epithelial cells (TECs) enables them to clear apoptotic cells (also known as efferocytosis), thereby protecting from acute kidney injury. Recently, we uncovered that KIM-1 binds directly to the α-subunit of heterotrimeric G12 protein (Gα12) and inhibits its activation by reactive oxygen species during renal ischemia-reperfusion injury (Ismail OZ, Zhang X, Wei J, Haig A, Denker BM, Suri RS, Sener A, Gunaratnam L. Am J Pathol 185: 1207-1215, 2015). Here, we investigated the role that Gα12 plays in KIM-1-mediated efferocytosis by TECs. We showed that KIM-1 remains bound to Gα12 and suppresses its activity during phagocytosis. When we silenced Gα12 expression using small interefering RNA, KIM-1-mediated engulfment of apoptotic cells was increased significantly; in contrast overexpression of constitutively active Gα12 (QL12) resulted in inhibition of efferocytosis. Inhibition of RhoA, a key effector of Gα12, using a chemical inhibitor or expression of dominant-negative RhoA, had the same effect as inhibition of Gα12 on efferocytosis. Consistent with this, silencing Gα12 suppressed active RhoA in KIM-1-expressing cells. Finally, using primary TECs from Kim-1+/+ and Kim-1-/- mice, we confirmed that engulfment of apoptotic cells requires KIM-1 expression and that silencing Gα12 enhanced efferocytosis by primary TECs. Our data reveal a previously unknown role for Gα12 in regulating efferocytosis and that renal TECs require KIM-1 to mediate this process. These results may have therapeutic implications given the known harmful role of Gα12 in acute kidney injury.


G protein; Gα12; kidney; kidney injury molecule-1 (KIM-1); phagocytosis

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