1. Academic Validation
  2. Protective Effect of Penetratin Analogue-Tagged SOD1 on Cisplatin-Induced Nephrotoxicity through Inhibiting Oxidative Stress and JNK/p38 MAPK Signaling Pathway

Protective Effect of Penetratin Analogue-Tagged SOD1 on Cisplatin-Induced Nephrotoxicity through Inhibiting Oxidative Stress and JNK/p38 MAPK Signaling Pathway

  • Oxid Med Cell Longev. 2021 Aug 21;2021:5526053. doi: 10.1155/2021/5526053.
Xiao-Lu Wang 1 Liang Wang 2 Fo-Lan Lin 1 Si-Si Li 1 Ting-Xuan Lin 1 Ren-Wang Jiang 1 3
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research and International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou 510632, China.
  • 2 Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
  • 3 Shengshitaiyan (Guangdong) Health Tech Ltd., Nanhai District, Foshan 528231, China.
Abstract

Copper/zinc superoxide dismutase (SOD1) can clear cisplatin- (CP-) induced excessive Reactive Oxygen Species (ROS), but exogenous SOD1 cannot enter cells because of its low biomembrane permeability. Cell-penetrating Peptides (CPPs) can rapidly cross plasma membranes. This study is aimed at identifying an efficient and stable CPP-SOD1 and investigating its effects on CP-induced nephrotoxicity. We recombined SOD1 with 14 different CPPs and purified them using an NTA-Ni2+ column. In in vitro experiments, CPPs-SOD1 cell membrane penetration ability and JNK/p38 MAPK signaling pathway were evaluated using Western blotting. ROS production, mitochondrial membrane potential (MMP), and cell Apoptosis were determined using flow cytometry and immunofluorescence staining in VERO and HK-2 cells. For in vivo experiments, mice were administered PSF-SOD1 for 2 h before cotreatment with a single CP injection for an additional 4 days. Blood and kidney samples were collected for renal function assessment (creatinine, urea nitrogen, histopathology, TUNEL assay, and JNK/p38 MAPK signaling pathway). Compared with TAT-SOD1, we found that PSF-SOD1 is more efficient at crossing the cell membrane and is stable after transduction into cells. Pretreatment with PSF-SOD1 inhibited CP-induced Apoptosis, ROS generation, and JNK/p38 MAPK activation and restored CP-induced MMP loss in VERO and HK-2 kidney cells. Treatment of mice with PSF-SOD1 inhibited CP-induced serum creatinine, blood urea nitrogen elevation, and JNK/p38 MAPK activation. H&E staining and TUNEL assay indicated that kidney tissue damage was alleviated following PSF-SOD1 pretreatment. Overall, PSF-SOD1 ameliorated CP-induced renal damage by partially reducing oxidative stress and cell Apoptosis by regulating JNK/p38 MAPK signaling pathway and might be a better cytoprotective agent than TAT-SOD1.

Figures
Products