Korean J Physiol Pharmacol.  2018 Sep;22(5):567-575. 10.4196/kjpp.2018.22.5.567.

Carbon monoxide releasing molecule-2 protects mice against acute kidney injury through inhibition of ER stress

• Uddin MJ
• Pak ES
• Ha H

• KMID: 2419006
• DOI: http://doi.org/10.4196/kjpp.2018.22.5.567

Abstract

Acute kidney injury (AKI), which is defined as a rapid decline of renal function, becomes common and recently recognized to be closely intertwined with chronic kidney diseases. Current treatment for AKI is largely supportive, and endoplasmic reticulum (ER) stress has emerged as a novel mediator of AKI. Since carbon monoxide attenuates ER stress, the objective of the present study aimed to determine the protective effect of carbon monoxide releasing molecule-2 (CORM2) on AKI associated with ER stress. Kidney injury was induced after LPS (15 mg/kg) treatment at 12 to 24 h in C57BL/6J mice. Pretreatment of CORM2 (30 mg/kg) effectively prevented LPS-induced oxidative stress and inflammation during AKI in mice. CORM2 treatment also effectively inhibited LPS-induced ER stress in AKI mice. In order to confirm effect of CO on the pathophysiological role of tubular epithelial cells in AKI, we used mProx24 cells. Pretreatment of CORM2 attenuated LPS-induced ER stress, oxidative stress, and inflammation in mProx24 cells. These data suggest that CO therapy may prevent ER stress-mediated AKI.

Keyword

Acute kidney injury; Carbon monoxide; ER stress; Oxidative stress

MeSH Terms

Acute Kidney Injury*
Animals
Carbon Monoxide*
Carbon*
Endoplasmic Reticulum
Epithelial Cells
Inflammation
Kidney
Mice*
Oxidative Stress
Renal Insufficiency, Chronic
Carbon
Carbon Monoxide

Figure

• 

  Fig. 1 CORM2 attenuates LPS-induced kidney injury. To fix the optimum time required for AKI induction, mice were treated with LPS (15 mg/kg) in a time dependent manner (0, 6, 12, 24 h). (A) Kidney weight/body weight (g), (B) Plasma creatinine (mg/dl), and (C) Plasma cystatin C (ng/ml). After fixing proper AKI induction time as 18 h, we pretreated mice with CORM2 (30 mg/kg) and then treated with LPS (15 mg/kg) for 18 h. (D) Plasma creatinine (mg/dl), (E) Plasma cystatin C (ng/ml), and (F) Tubular injury marker, plasma Kim1 (pg/ml). Data are presented as means±SE of 5–8 mice/group; *p<0.05 vs. control, †p<0.05 vs. LPS.

• 

  Fig. 2 CORM2 attenuates LPS-induced inflammation in kidney. (A) pNF-κB protein expression in the kidney was measured using western blotting. (B) Band intensities were measured using ImageJ software. (C, D) Paraffin-embedded kidney sections were stained with anti-F4/80 antibodies (1:200; original magnification: 100×; scale bar: 100 µm), and arrow marks represents the macrophage infiltration. (E) The mRNA levels of inflammation markers such as TNFα, MCP1, iNOS, and ICAM1 in kidney tissue were measured using real-time PCR. Data are presented as means±SE of 5–8 mice/group; *p<0.05 vs. control, †p<0.05 vs. LPS. (F) The mRNA levels of inflammation markers such as TNFa, MCP1, iNOS, and ICAM1 in mProx cells were measured using real-time PCR. Data are presented as means±SE, n=4; *p<0.05 vs. control, †p<0.05 vs. LPS.

• 

  Fig. 3 CORM2 inhibits LPS-induced ER stress in kidney. (A) pJNK protein expression was measured in the kidney using western blotting, and (B) band intensities were measured using ImageJ software. (C) CHOP protein expression was measured in the kidney using western blotting, and (D) band intensities were measured using ImageJ software. (E) ER stress markers such as sXBP1, Edem1, and GRP78 mRNA levels were measured in kidney tissue using realtime PCR. (A–E) Data are presented as means±SE of 5–8 mice/group; *p<0.05 vs. control, †p<0.05 vs. LPS. (F) The mRNA levels of ER stress markers such as sXBP1, Edem1, and GRP78 in mProx cells were measured using real-time PCR. Data are presented as means±SE, n=4; *p·0.05 vs. control, †p<0.05 vs. LPS.

• 

  Fig. 4 CORM2 inhibits LPS-induced ER stress through suppression of ROS generation. (A) Plasma LPO (µM), and (B) Kidney LPO (µM/mg tissue). (C) Paraffin-embedded kidney sections were stained with anti-nitrotyrosine antibodies (1:200; original magnification: 200×; scale bar: 100 µm), and arrow marks represents the accumulation of nitrotyrosine (brown color) on cytosol. (D) Frozen kidney sections were stained with DHE dye (5 µM for 10 min; original magnification: 100×; scale bar: 50 µm), and red color indicates the accumulation of ROS. The mRNA levels of antioxidant genes such as (E) Catalase, (F) Prx1, and (G) NRF2, HO1, and NQO1 in kidney tissue were measured using real-time PCR. (A–G) Data are presented as means±SE of 5–8 mice/group; *p<0.05 vs. control, †p<0.05 vs. LPS. (H) The mRNA levels of antioxidant genes such as NRF2, HO1, and NQO1 in mProx cells were measured using real-time PCR. Data are presented as means±SE, n=4; *p<0.05 vs. control, †p<0.05 vs. LPS.

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