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Volume 85, Issue 4, Pages (April 2014)

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1 Volume 85, Issue 4, Pages 871-879 (April 2014)
The cyclin-dependent kinase inhibitor p21 is essential for the beneficial effects of renal ischemic preconditioning on renal ischemia/reperfusion injury in mice  Satoshi Nishioka, Daisuke Nakano, Kento Kitada, Tadashi Sofue, Hiroyuki Ohsaki, Kumiko Moriwaki, Taiga Hara, Koji Ohmori, Masakazu Kohno, Akira Nishiyama  Kidney International  Volume 85, Issue 4, Pages (April 2014) DOI: /ki Copyright © 2014 International Society of Nephrology Terms and Conditions

2 Figure 1 Renal function, histology, and percent survival of mice subjected to ischemic-preconditioned (IPC) ischemia/reperfusion (I/R; n=3–7). Increases in blood urea nitrogen (BUN) caused by I/R were significantly greater in p21 knockout (p21-KO) mice than in wild-type mice (a). I/R-induced injury in the cortex was apparent in p21-KO mice (d; top panels). The S3 segment of proximal tubules was damaged in wild-type and p21-KO mice (d; bottom panels), and was more severe in p21-KO mice (b, d). Renal dysfunction caused by I/R was significantly suppressed by IPC in wild-type mice, but not in p21-KO mice (a, b, d). IPC improved the survival rate after I/R injury in wild-type mice, but not in p21-KO mice (c). *P<0.05 versus sham within each strain; #P<0.05 versus I/R within each strain; †P<0.05 versus the same treatment in wild-type mice. Bars=50μm. HE, hematoxylin and eosin. Kidney International  , DOI: ( /ki ) Copyright © 2014 International Society of Nephrology Terms and Conditions

3 Figure 2 Time course of changes in renal function, histology, and renal fibrosis following 30min of ischemia/reperfusion (I/R) in wild-type mice and 25min of I/R in p21 knockout (p21-KO) mice (n=4–7). Twenty-five minutes of I/R in p21-KO mice induced a similar severity of acute kidney injury (AKI) compared with 30min of I/R in wild-type mice at 24h after reperfusion. AKI (a, b) and the subsequent renal fibrosis (c, d) caused by I/R were significantly suppressed by IPC in wild-type mice, but not in p21-KO mice. *P<0.05 versus sham within each strain; #P<0.05 versus I/R within each strain. Bars=50μm. Kidney International  , DOI: ( /ki ) Copyright © 2014 International Society of Nephrology Terms and Conditions

4 Figure 3 Evaluation of p21 expression before and after ischemia/reperfusion (I/R; n=3–6). I/R with or without ischemic preconditioning (IPC) induced p21 mRNA expression (a) and anti-p21 antibody–positive tubules (b and arrows in c) in wild-type mice. IPC also stimulated the induction of p21 mRNA expression before ischemia (a). Some tubular cells showed extranuclear immunoreactivity (d). Several interstitial cells were positively stained with the anti-p21 antibody (e). #P<0.05 versus I/R within each strain. Bars=50μm in c, and 20μm in d, e. Kidney International  , DOI: ( /ki ) Copyright © 2014 International Society of Nephrology Terms and Conditions

5 Figure 4 Evaluation of proliferating cells before and after ischemia/reperfusion (I/R; n=4–6). The number of Ki-67-positive tubular cells was decreased by ischemic preconditioning (IPC) before the onset of I/R in wild-type mice, but not in p21-KO mice. The number of Ki-67-positive tubular cells was increased by I/R, with or without IPC, in wild-type mice (top). IPC accelerated the onset of tubular proliferation after I/R in wild-type mice (top), but not in p21-KO mice (bottom). *P<0.05 versus sham within each strain. Bars=50μm. Kidney International  , DOI: ( /ki ) Copyright © 2014 International Society of Nephrology Terms and Conditions

6 Figure 5 Effects of ischemic preconditioning (IPC) on the number of cells in the G1 phase in Fucci G1-red596 mice (n=3). Cells in Fucci G1-red596 mice show an increase in red fluorescence during the G1 phase. Intravital imaging of the kidney after IPC showed an increase in the number of proximal tubular cells with high red fluorescence in nuclei (a). Cells in the distal nephron (DT; distinguished by green auto-fluorescence) showed high fluorescence in both groups. Flow cytometry confirmed that IPC increased the proportion of cells in the G1 phase of isolated kidney cells (b). Kidney International  , DOI: ( /ki ) Copyright © 2014 International Society of Nephrology Terms and Conditions


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