title: Lysophosphatidic acid prevents renal ischemia-reperfusion injury by inhibition of apoptosis and complement activation.
abstract: Renal ischemia-reperfusion (I/R) injury is an important cause of acute renal failure as observed after renal transplantation, major surgery, trauma, and septic as well as hemorrhagic shock. We previously showed that the inhibition of apoptosis is protective against renal I/R injury, indicating that apoptotic cell-death is an important feature of I/R injury. Lysophosphatidic acid (LPA) is an endogenous phospholipid growth factor with anti-apoptotic properties. This tempted us to investigate the effects of exogenous LPA in a murine model of renal I/R injury. LPA administered at the time of reperfusion dose dependently inhibited renal apoptosis as evaluated by the presence of internucleosomal DNA cleavage. I/R-induced renal apoptosis was only present in tubular epithelial cells with evident disruption of brush border as assessed by immunohistochemistry for active caspase-7 and filamentous actin, respectively. LPA treatment specifically prevented tubular epithelial cell apoptosis but also reduced the I/R-induced loss of brush-border integrity. Besides, LPA showed strong anti-inflammatory effects, inhibiting the renal expression of tumor necrosis factor-alpha and abrogating the influx of neutrophils. Next, LPA dose dependently inhibited activation of the complement system. Moreover, treatment with LPA abrogated the loss of renal function in the course of renal I/R. This study is the first to show that administration of the phospholipid LPA prevents I/R injury, abrogating apoptosis and inflammation. Moreover, exogenous LPA is capable of preventing organ failure because of an ischemic insult and thus may provide new means to treat clinical conditions associated with I/R injury in the kidney and potentially also in other organs.
authors.affiliation: Department of General Surgery, Nutrition, and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: de Vries
authors.forename: Robert A
authors.initials: RA
authors.lastname: Matthijsen
authors.forename: Annemarie A J H M
authors.initials: AA
authors.lastname: van Bijnen
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D003167:Complement Activation; D003176:Complement C3 / Q000378:metabolism; D003183:Complement C6 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D003176:Complement C3; D003183:Complement C6; D008246:Lysophospholipids; D014409:Tumor Necrosis Factor-alpha; C505520:CASP7 protein, human; C505524:Casp7 protein, mouse; D053179:Caspase 7; D020169:Caspases