Penehyclidine Hydrochloride Pretreatment Ameliorates Rhabdomyolysis-Induced AKI by Activating the Nrf2/HO-1 Pathway and Alleviating [corrected] Endoplasmic Reticulum Stress in Rats. The.

Wei Zhao,Jinghua Wang,Guangli Wu,Xudong Huang,Yunshuang Chen,Lihui Wang,Lixia Zhang,Xinjun Yang,Salvatore V Pizzo

doi:10.1371/journal.pone.0151158

Abstract

Acute kidney injury (AKI) is one of the most severe complications of rhabdomyolysis (RM). The underlying mechanisms and potential preventions need to be investigated. Penehyclidine hydrochloride (PHC) was reported to ameliorate renal ischemia-reperfusion injury, but the effect of PHC on RM-reduced AKI is unknown. In this study, we established a rat model of RM-induced AKI using an intramuscular glycerol injection in the hind limbs. Rats were pretreated with PHC before the glycerol injection, and the heme oxygenase-1 (HO-1) inhibitor ZnPP was introduced to evaluate the effect of HO-1 on RM-induced AKI. PHC pretreatment ameliorated the pathological renal injury and renal dysfunction, and decreased the renal apoptosis rate in RM-induced AKI. PHC significantly up-regulated HO-1 expression, increased HO-1 enzymatic activity and decreased the accumulation of myoglobin in renal tissues. This effect was partly inhibited by ZnPP. PHC pretreatment also effectively up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) and down-regulated glucose regulated protein 78 (GRP78) and caspase-12 at both the gene and protein levels. These results suggest that the protective effects of PHC pretreatment on RM-induced AKI occur at least in part through activating the Nrf2/HO-1 pathway and alleviating endoplasmic reticulum stress (ERS) in rat renal tissues.

Highlights

Rhabdomyolysis (RM) is a syndrome characterized by skeletal muscle degeneration and muscle enzyme leakage [1]
Serum analysis shows, compared with group Penehyclidine hydrochloride (PHC), urea nitrogen (BUN) and Cr were significantly higher in groups Acute kidney injury (AKI), ZnPP and PHC+ZnPP at any time point (P
We have shown that PHC preconditioning remarkably ameliorated rhabdomyolysis-induced AKI in rats by up-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and inhibiting endoplasmic reticulum stress (ERS) in renal tissues

Summary

Introduction

Rhabdomyolysis (RM) is a syndrome characterized by skeletal muscle degeneration and muscle enzyme leakage [1]. The development of RM is associated with causes such as crush syndrome, exhaustive exercise, medications, infections and toxins [2,3,4,5]. Acute kidney injury (AKI) is one of the most severe complications of RM. Almost 15% of patients with RM will develop AKI [6], and 5–15% of AKI cases are attributed to RM [7].

Methods

Results

Discussion

Conclusion