Poly(ADP-ribose) polymerase 1 activation links ischemic acute kidney injury to interstitial fibrosis.
Inactivation of poly(ADP-ribose) polymerase 1 (PARP1) has been found to be protective in several disease models; however, the role of PARP1 in acute kidney injury-induced interstitial fibrosis has not been studied. Herein, we tested whether PARP1 inactivation by treatment with PJ34 (a PARP1 inactivator; 10 mg/kg body weight/day, intraperitoneal implantation of a miniosmotic pump at 2 days after the onset) contributed to the decrease in interstitial fibrosis induced by ischemia-reperfusion injury (IRI) in mouse kidneys. IRI increased PARP1 activation represented by poly(ADP-ribose) expression from 4 to 16 days postinjury, whereas treatment with PJ34 at 2 days after the onset efficaciously abolished the increase in PARP1 activation at 4, 8 and 16 days after IRI. Pharmacological inactivation of PARP1 significantly reduced interstitial fibrosis as represented by the collagen deposition and transforming growth factor-β1 level at 8 and 16 days after IRI. Consistent with collagen deposition, myofibroblast activation represented by α-smooth muscle actin expression was also reduced by PARP1 inactivation at 8 and 16 days after IRI. Furthermore, IRI enhanced macrophage influx, but PARP1 inactivaton remarkably reduced macrophage influx for 4 through 16 days after the injury. Among the chemoattractants for monocytes/macrophages and neutrophils, monocyte chemotactic protein-1 (MCP-1) production in IRI kidneys was significantly reduced by PARP1 inactivation from 4 to 16 days postinjury. These data demonstrate that PARP1 activation contributes to IRI-induced MCP-1 production and in turn to macrophage influx, resulting in the promotion of interstitial fibrosis.
Department of Anatomy, Jeju National University School of Medicine, Jeju, 690-756, Republic of Korea.
Sang Pil
SP
Yoon
Jinu
J
Kim
D000199:Actins / Q000378:metabolism; D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
D000199:Actins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C544013:alpha-smooth muscle actin, mouse; D003094:Collagen; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases