Poly(ADP-ribose) polymerase 1 activation links ischemic acute kidney injury to interstitial fibrosis.

Abstract

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.