Pin1 aggravates renal injury induced by ischemia and reperfusion in rats via Nrf2/HO-1 mediated endoplasmic reticulum stress

Yu, Honglin; Jiang, Guanjun; Hu, Wei; Xu, Changgeng

doi:10.1590/acb370101

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ORIGINAL ARTICLE • Acta Cir. Bras. 37 (1) • 2022 • https://doi.org/10.1590/acb370101 copy

Pin1 aggravates renal injury induced by ischemia and reperfusion in rats via Nrf2/HO-1 mediated endoplasmic reticulum stress

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Purpose:

To investigate the role of peptidyl-prolyl cis/trans isomerase 1 (Pin1) on renal ischemia-reperfusion (I/R) injury and underlying mechanism.

Methods:

By establishing the in vitro and in vivo models of renal I/R, the role of Pin1 was explored by using molecular assays.

Results:

In renal I/R, endogenous Pin1 level was up-regulated in I/R-impaired kidney. Suppression of Pin1 with juglone afforded protection against I/R-mediated kidney dysfunction, and reduced I/R-induced endoplasmic reticulum (ER) stress in vivo. Consistent with the in vivo results, repression of Pin1 with juglone or gene knockdown with si-Pin1 conferred cytoprotection and restricted hypoxia/reoxygenation (H/R)-driven ER stress in HK-2 cells. Simultaneously, further study uncovered that Nrf-2/HO-1 signals was the association between Pin1 and ER stress in response to renal I/R. In addition, Nrf-2/HO-1 signal pathway was inactivated after kidney exposed to I/R, as indicated by the down-regulation of Nrf-2/HO-1 levels. Furthermore, inhibition of Pin1 remarkably rescued the inactivation ofNrf-2/HO-1.

Conclusions:

Pin1 modulated I/R-mediated kidney injury in ER stress manner dependent on Nrf2-HO-1 pathway in I/R injury.

Key words
NIMA-Interacting Peptidylprolyl Isomerase; Ischemia; Reperfusion; NF-E2-Related Factor 2; Heme Oxygenase-1; Endoplasmic Reticulum Stress

Authorship

Honglin Yu

MD. Department of Radiology – The First Affiliated Hospital of Anhui Medical University – Anhui, China.The First Affiliated Hospital of Anhui Medical UniversityChinaAnhui, ChinaMD. Department of Radiology – The First Affiliated Hospital of Anhui Medical University – Anhui, China.

Authors’ contribution Conception and design of the study: Hu W and Xu C; Critical revision: Hu W and Xu C; Technical procedures: Yu H and Jiang G; Design of the study: Yu H and Jiang G; Interpretation of data: Yu H and Jiang G; Statistical analysis: Yu H; Manuscript preparation: Yu H. #The authors contributed equally to this work.

https://orcid.org/0000-0001-5330-2182

Guanjun Jiang

MD. Department of Urology – The Fifth Hospital of Wuhan – Wuhan, China.The Fifth Hospital of WuhanChinaWuhan, ChinaMD. Department of Urology – The Fifth Hospital of Wuhan – Wuhan, China.

https://orcid.org/0000-0002-4076-1547

Wei Hu ^**Corresponding author: huwei_abc970642@163.com | (+86) 18007344154

MD. Department of Andrology – The First Affiliated Hospital – Hengyang Medical School – University of South China – Hunan, China.University of South ChinaChinaHunan, ChinaMD. Department of Andrology – The First Affiliated Hospital – Hengyang Medical School – University of South China – Hunan, China.

https://orcid.org/0000-0002-8481-5228

Changgeng Xu

MD. Department of Urology – The Central Hospital of Wuhan – Tongji Medical College – Huazhong University of Science and Technology – Hubei, China.Huazhong University of Science and TechnologyChinaHubei, ChinaMD. Department of Urology – The Central Hospital of Wuhan – Tongji Medical College – Huazhong University of Science and Technology – Hubei, China.

https://orcid.org/0000-0003-4935-6932

*Corresponding author: huwei_abc970642@163.com | (+86) 18007344154

Authors’ contribution

Conception and design of the study: Hu W and Xu C; Critical revision: Hu W and Xu C; Technical procedures: Yu H and Jiang G; Design of the study: Yu H and Jiang G; Interpretation of data: Yu H and Jiang G; Statistical analysis: Yu H; Manuscript preparation: Yu H. #The authors contributed equally to this work.

Conflict of interest: Nothing to declare.

SCIMAGO INSTITUTIONS RANKINGS

MD. Department of Urology – The Fifth Hospital of Wuhan – Wuhan, China.The Fifth Hospital of WuhanChinaWuhan, ChinaMD. Department of Urology – The Fifth Hospital of Wuhan – Wuhan, China.

Figures

Figures (6)

Thumbnail

Figure 1
Pin1 expression was up-regulated in the kidney subjected to I/R in rats. (a) Pin1 mRNA level was detected by RT-PCR after ischemia 45 min and reperfusion 6, 12 and 24 h, respectively. (b, c) Pin1 protein level was detected by western blot and the quantification was performed. (d, e) Serum Cr and BUN level were detected after ischemia 45 min and reperfusion 6, 12 and 24 h, respectively. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to the Sham group.

Thumbnail

Figure 2
Pin1 inhibitor protected kidney against I/R injury in rats. (a, b) The effect of Juglone at different concentration (2.5, 5 and 10 mg·kg^–1) on renal function in rats subjected to ischemia 45 min and reperfusion 24 h. (c) The effect of Juglone at different concentration (2.5, 5 and 10 mg·kg^–1) on renal structure damage detected by H&E staining (400×). Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to Sham group;

Thumbnail

Figure 3
Pin1 inhibitor ameliorates endoplasmic reticulum stress and Nrf-2/HO1 pathway. (a) The effect of Pin1 inhibitor (10 mg·kg^–1) on Pin1 expression in rats exposed to renal ischemia 45 min and reperfusion 24 h, and quantification was performed. (b, c) The effect of Pin1 inhibitor (10 mg·kg^–1) on Nrf2-HO-1 pathway expression in rats exposed to renal ischemia 45 min and reperfusion 24 h, and quantification was performed. (d–f) The effect of Pin1 inhibitor (10 mg·kg^–1) on GRP78, eIF2α and CHOP expression in rats exposed to renal ischemia 45 min and reperfusion 24 h, and quantification was performed. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to Sham group;

Thumbnail

Figure 4
Pin1 expression was elevated during H/R process in HK-2 cells and Pin1 inhibitor could protected cell ability against H/R. (a) Cell viability was detected at hypoxia 12 h and reoxygenation 2, 4 and 6 h, respectively. (b) Pin1 mRNA level was detected by RT-PCR after hypoxia 12 h and reoxygenation 2, 4 and 6 h, respectively. (c, d) Pin1 protein level was detected by western blot and the quantification was performed. (e) Cell viability was detected with the treatment of different concentration of Pin1 inhibitor at hypoxia 12 h and reoxygenation 6 h. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to control group;

Thumbnail

Figure 5
Pin1 silence alleviated endoplasmic reticulum stress induced by H/R. (a) HK-2 cells were transfected with negative control or si-RNA for Pin1 and subjected to H/R after transfection 24 h. Western blot was performed for Pin1 expression and quantification relative to control group. (b–d) The effect of si-Pin1 on the expression of GRP78, p-eIF2α, and CHOP after H/R and quantification relative to control group. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to control group;

Thumbnail

Figure 6
Pin1 regulates endoplasmic reticulum stress induced by H/R through Nrf2/HO-1 pathway. HK-2 cells were treated with Pin1 inhibitor (10 μmol·L^–1) for 1 h, followed by H/R, with or without pretreatment with Nrf2 inhibitor ML385 (5 μmol·L^–1). (a, b) The expression of Nrf2/HO-1 pathway was detected by western blot and quantification was performed. (c–e) The expression of GRP78, p-eIF2α, and CHOP were detected by western blot and quantification was performed relative to control group. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to control group;

Figure 1 Pin1 expression was up-regulated in the kidney subjected to I/R in rats. (a) Pin1 mRNA level was detected by RT-PCR after ischemia 45 min and reperfusion 6, 12 and 24 h, respectively. (b, c) Pin1 protein level was detected by western blot and the quantification was performed. (d, e) Serum Cr and BUN level were detected after ischemia 45 min and reperfusion 6, 12 and 24 h, respectively. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to the Sham group.

Figure 2 Pin1 inhibitor protected kidney against I/R injury in rats. (a, b) The effect of Juglone at different concentration (2.5, 5 and 10 mg·kg^–1) on renal function in rats subjected to ischemia 45 min and reperfusion 24 h. (c) The effect of Juglone at different concentration (2.5, 5 and 10 mg·kg^–1) on renal structure damage detected by H&E staining (400×). Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to Sham group;

Figure 3 Pin1 inhibitor ameliorates endoplasmic reticulum stress and Nrf-2/HO1 pathway. (a) The effect of Pin1 inhibitor (10 mg·kg^–1) on Pin1 expression in rats exposed to renal ischemia 45 min and reperfusion 24 h, and quantification was performed. (b, c) The effect of Pin1 inhibitor (10 mg·kg^–1) on Nrf2-HO-1 pathway expression in rats exposed to renal ischemia 45 min and reperfusion 24 h, and quantification was performed. (d–f) The effect of Pin1 inhibitor (10 mg·kg^–1) on GRP78, eIF2α and CHOP expression in rats exposed to renal ischemia 45 min and reperfusion 24 h, and quantification was performed. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to Sham group;

Figure 4 Pin1 expression was elevated during H/R process in HK-2 cells and Pin1 inhibitor could protected cell ability against H/R. (a) Cell viability was detected at hypoxia 12 h and reoxygenation 2, 4 and 6 h, respectively. (b) Pin1 mRNA level was detected by RT-PCR after hypoxia 12 h and reoxygenation 2, 4 and 6 h, respectively. (c, d) Pin1 protein level was detected by western blot and the quantification was performed. (e) Cell viability was detected with the treatment of different concentration of Pin1 inhibitor at hypoxia 12 h and reoxygenation 6 h. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to control group;

Figure 5 Pin1 silence alleviated endoplasmic reticulum stress induced by H/R. (a) HK-2 cells were transfected with negative control or si-RNA for Pin1 and subjected to H/R after transfection 24 h. Western blot was performed for Pin1 expression and quantification relative to control group. (b–d) The effect of si-Pin1 on the expression of GRP78, p-eIF2α, and CHOP after H/R and quantification relative to control group. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to control group;

Figure 6 Pin1 regulates endoplasmic reticulum stress induced by H/R through Nrf2/HO-1 pathway. HK-2 cells were treated with Pin1 inhibitor (10 μmol·L^–1) for 1 h, followed by H/R, with or without pretreatment with Nrf2 inhibitor ML385 (5 μmol·L^–1). (a, b) The expression of Nrf2/HO-1 pathway was detected by western blot and quantification was performed. (c–e) The expression of GRP78, p-eIF2α, and CHOP were detected by western blot and quantification was performed relative to control group. Values were expressed as the mean ± SEM (n = 8). *P < 0.05, relative to control group;

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Pin1 aggravates renal injury induced by ischemia and reperfusion in rats via Nrf2/HO-1 mediated endoplasmic reticulum stress

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[1] *Corresponding author: huwei_abc970642@163.com | (+86) 18007344154