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2016 ; 310
(7
): F607-F620
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G protein ?(12) (G?(12)) is a negative regulator of kidney injury
molecule-1-mediated efferocytosis
#MMPMID26697979
Ismail OZ
; Zhang X
; Bonventre JV
; Gunaratnam L
Am J Physiol Renal Physiol
2016[Apr]; 310
(7
): F607-F620
PMID26697979
show ga
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 ?-subunit of
heterotrimeric G(12) protein (G?(12)) 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 G?(12) plays in KIM-1-mediated
efferocytosis by TECs. We showed that KIM-1 remains bound to G?(12) and
suppresses its activity during phagocytosis. When we silenced G?(12) expression
using small interefering RNA, KIM-1-mediated engulfment of apoptotic cells was
increased significantly; in contrast overexpression of constitutively active
G?(12) (QLG?(12)) resulted in inhibition of efferocytosis. Inhibition of RhoA, a
key effector of G?(12), using a chemical inhibitor or expression of
dominant-negative RhoA, had the same effect as inhibition of G?(12) on
efferocytosis. Consistent with this, silencing G?(12) 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 G?(12) enhanced efferocytosis by primary TECs. Our
data reveal a previously unknown role for G?(12) 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 G?(12) in acute kidney
injury.
|Animals
[MESH]
|Cell Survival/physiology
[MESH]
|Epithelial Cells/metabolism
[MESH]
|GTP-Binding Protein alpha Subunits, G12-G13/*metabolism
[MESH]
|HEK293 Cells
[MESH]
|Hepatitis A Virus Cellular Receptor 1/genetics/*metabolism
[MESH]
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