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

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/Rinduced 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 of Nrf-2/HO-1. Conclusion: Pin1 modulated I/R-mediated kidney injury in ER stress manner dependent on Nrf2-HO-1 pathway in I/R injury.

Naringenin Alleviates Renal Ischemia Reperfusion Injury by Suppressing ER Stress-Induced Pyroptosis and Apoptosis through Activating Nrf2/HO-1 Signaling Pathway

“…Next, subject members explored underlying mechanism by which NAR was capable of modulating ER stress. Since NAR could notably alleviate ER stress [ 34 , 35 ] and Nrf2/HO-1 pathway had been demonstrated to be of great importance in regulating ER stress [ 36 , 37 ], we examined the expression of relevant proteins after NAR usage in vitro. The protein expressions of Nrf2 and HO-1 were indeed visibly suppressed by H/R treatment, while pretreatment of NRG reactivated Nrf2/HO-1 signaling pathway in H/R injury ( Figure 8(a) ).…”

“…In this research, we observed that the crucial reason for NRG's ability to preserve kidney against I/R injury was its advantages in inhibiting pyroptosis and apoptosis by effectively reducing ER stress. It was frequently demonstrated that Nrf2/HO-1 signaling pathway took a momentous part in moderating ER stress [ 36 , 37 , 72 ], and NRG had been confirmed to have a talent in regulating Nrf2/HO-1 pathway to exert its protective effects [ 73 – 75 ]. The western blot analysis authenticated that decreased protein levels of Nrf2 and HO-1 during renal I/R injury were elevated again after pretreatment of naringenin in animals and HK-2 cells.…”

“…The protein levels in different treatment groups confirmed that the administration of 4-PBA effectively restrained the expression of apoptotic markers including BAX and cleaved caspase-3, and the trend of Bcl-2 protein was elevated in the 4-PBA+H/R group (Figure 7(h)). [34,35] and Nrf2/HO-1 pathway had been demonstrated to be of great importance in regulating ER stress [36,37], we examined the expression of relevant proteins after NAR usage in vitro. The protein expressions of Nrf2 and HO-1 were indeed visibly suppressed by H/R treatment, while pretreatment of NRG reactivated Nrf2/HO-1 signaling pathway in H/R injury (Figure 8(a)).…”

The molecular mechanisms of peptidyl-prolyl cis/trans isomerase Pin1 and its relevance to kidney disease

“…Furthermore, Yu et al reported that Juglone or si-Pin1 protects against renal I/R-induced AKI by mitigating cellular damage and reducing the expression of ER stress markers, including GRP78, eIF2α, and CHOP. This protective effect is achieved by the downregulation of the Nrf-2/HO-1 pathway ( Yu et al, 2022 ). Future studies should investigate the association between Pin1 and additional pathological processes triggered by I/R-related AKI as well as AKI resulting from sepsis or other nephrotoxic events.…”

Acute kidney injury: exploring endoplasmic reticulum stress-mediated cell death

“…Renal IRI lead to the deactivation of the NRF2/HO-1 signaling pathway, along with an increased expression of GRP78, eIF2α, and CHOP protein. Activation of the NRF2/HO-1 signal limited the increase in levels of ERS-associated proteins, thereby relieving the impaired renal function and structural harm caused by IRI (Yu et al, 2022). Moreover, the involvement of connexin32 in IRI-induced AKI is crucial as it triggered the ROS/ERS/apoptosis signaling pathway.…”