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10.1073/pnas.1424313112 http://scihub22266oqcxt.onion/10.1073/pnas.1424313112 C4413320!4413320 !25848011     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\25848011 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Proc+Natl+Acad+Sci+U+S+A 2015 ; 112 (16 ): 5231-6 Nephropedia Template TP {{tp|p=25848011 |t=2015. Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions |pdf=|usr=}}{{25848011 }} gab.com Text Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions JO: Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=25848011 #FOAvip Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI. Twit Text FOAVip Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions ????Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=25848011 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25848011 #FOAvip English Wikipedia <ref>{{Cite pmid|25848011 }}</ref> Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions #MMPMID25848011 Pabla N ; Gibson AA ; Buege M ; Ong SS ; Li L ; Hu S ; Du G ; Sprowl JA ; Vasilyeva A ; Janke LJ ; Schlatter E ; Chen T ; Ciarimboli G ; Sparreboom A Proc Natl Acad Sci U S A 2015[Apr]; 112 (16 ): 5231-6 PMID25848011 show ga Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI. |*Cell Cycle Checkpoints/drug effects [MESH] |Acute Kidney Injury/*drug therapy/pathology [MESH] |Aminopyridines/pharmacology/therapeutic use [MESH] |Animals [MESH] |Cisplatin [MESH] |Cyclin-Dependent Kinase 4/*antagonists & inhibitors/metabolism [MESH] |Cyclin-Dependent Kinase 6/*antagonists & inhibitors/metabolism [MESH] |Disease Models, Animal [MESH] |Enzyme Activation/drug effects [MESH] |HEK293 Cells [MESH] |HeLa Cells [MESH] |Humans [MESH] |Kidney Tubules/drug effects/enzymology/pathology [MESH] |Mice [MESH] |Organic Cation Transport Proteins/*antagonists & inhibitors/deficiency/metabolism [MESH] |Organic Cation Transporter 2 [MESH] |Piperazines/pharmacology/therapeutic use [MESH] |Protective Agents/pharmacology/therapeutic use [MESH] |Purines/pharmacology/therapeutic use [MESH] |Pyridines/pharmacology/therapeutic use [MESH]Mitigation of acute kidney injury by cell-cycle inhibitors that suppre(epmc).pdf DeepDyve Pubget Overpricing