Adam Khader1, Weng-Lang Yang, Michael Kuncewitch, Asha Jacob, Jose M Prince, Jaya R Asirvatham, Jeffrey Nicastro, Gene F Coppa, Ping Wang. 1. 1 The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY. 2 Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY. 3 Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY. 4 Department of Pathology, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY. 5 Address correspondence to: Ping Wang, M.D., Center for Translational Research, Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030.
Abstract
BACKGROUND: Renal ischemia-reperfusion (I/R) is a major contributor to delayed graft function after renal transplantation. The pathophysiology of I/R can be summarized by a primary energy deficit during ischemia and a secondary phase of oxidative stress and inflammation. Sirtuin 1 is an energy-sensing enzyme involved in regulating multiple cellular functions. We hypothesized that stimulating Sirtuin 1 would increase mitochondrial biogenesis thereby enhancing energy metabolism and attenuating I/R-induced renal injury. METHODS: Adult male rats were subjected to 60 min of bilateral renal pedicle clamping. SRT1720 (5 mg/kg body weight) or vehicle (20% dimethyl sulfoxide in saline) was administered intravenously at reperfusion. Blood and renal tissues were collected 24 hr after reperfusion. RESULTS: Posttreatment with SRT1720 significantly improved renal histologic architecture, decreased apoptosis, and reduced serum aspartate aminotransferase and creatinine levels compared to the vehicle. Renal adenosine triphosphate (ATP) levels were reduced by 48% after I/R, whereas SRT1720 restored ATP to 77% of control. Further, SRT1720 reversed the loss of renal mitochondrial mass induced by I/R supported by an increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and its downstream mediators. SRT1720 also increased ATP levels and mitochondrial mass in human renal HK-2 cells. Moreover, SRT1720 decreased the levels of malondialdehyde, nitrotyrosine, and inducible nitric oxide synthase expression compared to the vehicle. A marked decrease in macrophage infiltration by SRT1720 treatment was associated with a decrease in tumor necrosis factor-α expression and a decrease in IκB-α degradation and nuclear factor-κB phosphorylation after I/R. CONCLUSION: SRT1720 treatment enhanced energy metabolism by stimulating mitochondrial biogenesis as well as decreasing nitrosative stress and inflammation, thereby attenuating I/R-induced renal injury.
BACKGROUND: Renal ischemia-reperfusion (I/R) is a major contributor to delayed graft function after renal transplantation. The pathophysiology of I/R can be summarized by a primary energy deficit during ischemia and a secondary phase of oxidative stress and inflammation. Sirtuin 1 is an energy-sensing enzyme involved in regulating multiple cellular functions. We hypothesized that stimulating Sirtuin 1 would increase mitochondrial biogenesis thereby enhancing energy metabolism and attenuating I/R-induced renal injury. METHODS: Adult male rats were subjected to 60 min of bilateral renal pedicle clamping. SRT1720 (5 mg/kg body weight) or vehicle (20% dimethyl sulfoxide in saline) was administered intravenously at reperfusion. Blood and renal tissues were collected 24 hr after reperfusion. RESULTS: Posttreatment with SRT1720 significantly improved renal histologic architecture, decreased apoptosis, and reduced serum aspartate aminotransferase and creatinine levels compared to the vehicle. Renal adenosine triphosphate (ATP) levels were reduced by 48% after I/R, whereas SRT1720 restored ATP to 77% of control. Further, SRT1720 reversed the loss of renal mitochondrial mass induced by I/R supported by an increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and its downstream mediators. SRT1720 also increased ATP levels and mitochondrial mass in human renal HK-2 cells. Moreover, SRT1720 decreased the levels of malondialdehyde, nitrotyrosine, and inducible nitric oxide synthase expression compared to the vehicle. A marked decrease in macrophage infiltration by SRT1720 treatment was associated with a decrease in tumor necrosis factor-α expression and a decrease in IκB-α degradation and nuclear factor-κB phosphorylation after I/R. CONCLUSION: SRT1720 treatment enhanced energy metabolism by stimulating mitochondrial biogenesis as well as decreasing nitrosative stress and inflammation, thereby attenuating I/R-induced renal injury.
Authors: Matthew H Levine; Zhonglin Wang; Haiyan Xiao; Jing Jiao; Liqing Wang; Tricia R Bhatti; Wayne W Hancock; Ulf H Beier Journal: Kidney Int Date: 2016-03-16 Impact factor: 10.612
Authors: Adam Khader; Weng-Lang Yang; Andrew Godwin; Jose M Prince; Jeffrey M Nicastro; Gene F Coppa; Ping Wang Journal: Crit Care Med Date: 2016-08 Impact factor: 7.598
Authors: Adam Khader; Weng-Lang Yang; Michael Kuncewitch; Jose M Prince; Philippe Marambaud; Jeffrey Nicastro; Gene F Coppa; Ping Wang Journal: J Surg Res Date: 2014-08-13 Impact factor: 2.192
Authors: Adam Khader; Weng-Lang Yang; Laura W Hansen; Salil R Rajayer; Jose M Prince; Jeffrey M Nicastro; Gene F Coppa; Ping Wang Journal: J Surg Res Date: 2017-07-10 Impact factor: 2.192
Authors: Laura W Hansen; Adam Khader; Weng-Lang Yang; Jose M Prince; Jeffrey M Nicastro; Gene F Coppa; Ping Wang Journal: Shock Date: 2016-04 Impact factor: 3.454