G protein, 12 (Gα12) is a negative regulator of kidney injury molecule-1-mediated efferocytosis.

G protein, 12 (Gα12) is a negative regulator of kidney injury molecule-1-mediated efferocytosis. Am J Physiol Renal Physiol. 2015 Dec 23;:ajprenal.00169.2015 Authors: Ismail O, Zhang X, Bonventre JV, Gunaratnam L Abstract 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 alpha subunit of heterotrimeric G12 protein (Gα12) and inhibits its activation by reactive oxygen species during renal ischemia-reperfusion injury. Here we investigated the role of 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 siRNA, KIM-1-mediated engulfment of apoptotic cells was increased significantly; in contrast overexpression of constitutively active Gα12 (QLGα12) 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(-/...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research