Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production.
Zhi-Feng LiuJingjing JiDong ZhengLei SuTianqing PengJing TangPublished in: Experimental & molecular medicine (2020)
To explore the role of calpain and its signaling pathway in lipopolysaccharide (LPS)-induced acute kidney injury (AKI), animal models of endotoxemia were established by administration of LPS to mice with endothelial-specific Capn4 knockout (TEK/Capn4-/-), mice with calpastatin (an endogenous calpain inhibitor) overexpression (Tg-CAST) and mice with myeloid-specific Capn4 knockout (LYZ/Capn4-/-). Mouse pulmonary microvascular endothelial cells (PMECs) were used as a model of the microvascular endothelium and were stimulated with LPS. Renal function, renal inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) expression, cellular apoptosis, plasma and renal levels of NO and reactive oxygen species (ROS), and phosphorylation of mitogen-activated protein kinase (MAPK) family members (p38, ERK1/2, and JNK1/2) were examined. Moreover, a calpain inhibitor, calpastatin overexpression adenoviruses and MAPK inhibitors were used. Significant renal dysfunction was induced by LPS stimulation, and recovery was observed in TEK/Capn4-/- and Tg-CAST mice but not in LYZ/Capn4-/- mice. Endothelial Capn4 knockout also abrogated the LPS-induced increases in renal iNOS expression, caspase-3 activity and apoptosis and plasma and renal NO and ROS levels but did not obviously affect renal eNOS expression. Moreover, LPS increased both calpain and caspase-3 activity, and only the expression of iNOS in PMECs was accompanied by increased phosphorylation of p38 and JNK. Inhibiting calpain activity or p38 phosphorylation alleviated the increased iNOS expression, NO/ROS production, and cellular apoptosis induced by LPS. These results suggest that endothelial calpain plays a protective role in LPS-induced AKI by inhibiting p38 phosphorylation, thus attenuating iNOS expression and further decreasing NO and ROS overproduction-induced endothelial apoptosis.
Keyphrases
- inflammatory response
- lps induced
- nitric oxide synthase
- signaling pathway
- cell death
- endothelial cells
- lipopolysaccharide induced
- acute kidney injury
- poor prognosis
- nitric oxide
- pi k akt
- reactive oxygen species
- oxidative stress
- cell cycle arrest
- induced apoptosis
- endoplasmic reticulum stress
- dna damage
- high glucose
- toll like receptor
- high fat diet induced
- wild type
- cell proliferation
- binding protein
- protein kinase
- cardiac surgery
- anti inflammatory
- long non coding rna
- vascular endothelial growth factor
- epithelial mesenchymal transition
- skeletal muscle
- acute myeloid leukemia
- dendritic cells
- drug induced
- transcription factor