RT Journal Article
SR Electronic
T1 G-Protein <em>βγ</em> Subunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 369
OP 377
DO 10.1124/mol.114.092346
VO 86
IS 4
A1 White, Sarah M.
A1 North, Lauren M.
A1 Haines, Emily
A1 Goldberg, Megan
A1 Sullivan, Lydia M.
A1 Pressly, Jeffrey D.
A1 Weber, David S.
A1 Park, Frank
A1 Regner, Kevin R.
YR 2014
UL http://molpharm.aspetjournals.org/content/86/4/369.abstract
AB Heterotrimeric G-proteins play a crucial role in the control of renal epithelial cell function during homeostasis and in response to injury. In this report, G-protein βγ subunit (Gβγ) dimer activity was evaluated during the process of tubular repair after renal ischemia-reperfusion injury (IRI) in male Sprague Dawley rats. Rats were treated with a small molecule inhibitor of Gβγ activity, gallein (30 or 100 mg/kg), 1 hour after reperfusion and every 24 hours for 3 additional days. After IRI, renal dysfunction was prolonged after the high-dose gallein treatment in comparison with vehicle treatment during the 7-day recovery period. Renal tubular repair in the outer medulla 7 days after IRI was significantly (P &lt; 0.001) attenuated after treatment with high-dose gallein (100 mg/kg) in comparison with low-dose gallein (30 mg/kg), or the vehicle and fluorescein control groups. Gallein treatment significantly reduced (P &lt; 0.05) the number of proliferating cell nuclear antigen–positive tubular epithelial cells at 24 hours after the ischemia-reperfusion phase in vivo. In vitro application of gallein on normal rat kidney (NRK-52E) proximal tubule cells significantly reduced (P &lt; 0.05) S-phase cell cycle entry compared with vehicle-treated cells as determined by 5′-bromo-2′-deoxyuridine incorporation. Taken together, these data suggest that Gβγ signaling contributes to the maintenance and repair of renal tubular epithelium and may be a novel therapeutic target for the development of drugs to treat acute kidney injury.