@article {569421, title = {A bioinformatics approach identifies signal transducer and activator of transcription-3 and checkpoint kinase 1 as upstream regulators of kidney injury molecule-1 after kidney injury.}, journal = {J Am Soc Nephrol}, volume = {25}, number = {1}, year = {2014}, month = {2014 Jan}, pages = {105-18}, abstract = { Kidney injury molecule-1 (KIM-1)/T cell Ig and mucin domain-containing protein-1 (TIM-1) is upregulated more than other proteins after AKI, and it is highly expressed in renal damage of various etiologies. In this capacity, KIM-1/TIM-1 acts as a phosphatidylserine receptor on the surface of injured proximal tubular epithelial cells, mediating phagocytosis of apoptotic cells, and it may also act as a costimulatory molecule for immune cells. Despite recognition of KIM-1 as an important therapeutic target for kidney disease, the regulators of KIM-1 transcription in the kidney remain unknown. Using a bioinformatics approach, we identified upstream regulators of KIM-1 after AKI. In response to tubular injury in rat and human kidneys or oxidant stress in human proximal tubular epithelial cells (HPTECs), KIM-1 expression increased significantly in a manner that corresponded temporally and regionally with increased phosphorylation of checkpoint kinase 1 (Chk1) and STAT3. Both ischemic and oxidant stress resulted in a dramatic increase in reactive oxygen species that phosphorylated and activated Chk1, which subsequently bound to STAT3, phosphorylating it at S727. Furthermore, STAT3 bound to the KIM-1 promoter after ischemic and oxidant stress, and pharmacological or genetic induction of STAT3 in HPTECs increased KIM-1 mRNA and protein levels. Conversely, inhibition of STAT3 using siRNAs or dominant negative mutants reduced KIM-1 expression in a kidney cancer cell line (769-P) that expresses high basal levels of KIM-1. These observations highlight Chk1 and STAT3 as critical upstream regulators of KIM-1 expression after AKI and may suggest novel approaches for therapeutic intervention. }, keywords = {Acute Kidney Injury, Animals, Cell Adhesion Molecules, Cell Line, Computational Biology, DNA Damage, Gene Expression Regulation, Humans, Kidney, Male, Membrane Glycoproteins, Oxidative Stress, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Protein Kinases, Rats, Rats, Wistar, Receptors, Virus, Reperfusion Injury, RNA, Messenger, RNA, Small Interfering, STAT3 Transcription Factor}, issn = {1533-3450}, doi = {10.1681/ASN.2013020161}, author = {Ajay, Amrendra Kumar and Kim, Tae-Min and Ramirez-Gonzalez, Victoria and Park, Peter J and Frank, David A and Vaidya, Vishal S} }