title: The cyclin-dependent kinase inhibitor p21 is essential for the beneficial effects of renal ischemic preconditioning on renal ischemia/reperfusion injury in mice.
abstract: The cyclin-dependent kinase inhibitor p21 plays important roles in chronic renal disorders; however, its roles in response to acute renal stress are unclear. Here we evaluated p21 in acute kidney injury and ischemic preconditioning using wild-type and p21 knockout mice that underwent renal ischemia followed by reperfusion. The decline in renal function and histological changes were worse in the knockout than in wild-type mice. Ischemia/reperfusion increased p21 expression in the kidney of wild-type mice compared with sham surgery, suggesting p21 may confer tolerance to ischemia/reperfusion injury. We next tested whether p21 is associated with the protective effect of ischemic preconditioning, an established method to reduce ischemia/reperfusion injury. Ischemic preconditioning attenuated ischemia/reperfusion injury in wild-type but not p21-knockout mice. This preconditioning decreased the number of proliferating tubular cells before but increased them at 24 h after ischemia/reperfusion in the kidneys of wild-type mice. In p21-knockout mice, ischemic preconditioning did not change the number of proliferating cells before but decreased them after ischemia/reperfusion. Ischemic preconditioning increased renal p21 expression and the number of cells in the G1 phase of the cell cycle before ischemia/reperfusion compared with sham surgery. Thus, renal p21 is essential for the beneficial effects of renal ischemic preconditioning. Transient cell cycle arrest induced by ischemic preconditioning by a p21-dependent pathway seems to be important for subsequent tubular cell proliferation after ischemia/reperfusion.
authors: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Satoshi
authors: S
authors: Nishioka
authors: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Daisuke
authors: D
authors: Nakano
authors: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Kento
authors: K
authors: Kitada
authors: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Tadashi
authors: T
authors: Sofue
authors: Department of Medical Technology, Faculty of Clinical Examination, Ehime Prefectural University of Health Sciences, Ehime, Japan.
authors: Hiroyuki
authors: H
authors: Ohsaki
authors: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Kumiko
authors: K
authors: Moriwaki
authors: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Taiga
authors: T
authors: Hara
authors: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Koji
authors: K
authors: Ohmori
authors: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Masakazu
authors: M
authors: Kohno
authors: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Akira
authors: A
authors: Nishiyama
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D059447:Cell Cycle Checkpoints; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D019194:Ischemic Preconditioning; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse