Abstract
Renal tubulointerstitial inflammation plays an important role in chronic kidney disease (CKD). Inflammation reduction is a good strategy to combat CKD. Oridonin, an ent-kaurane diterpenoid isolated from Rabdosia rubescens (Donglingcao), is considered as an effective natural candidate for the treatment of anti-inflammatory, antiviral, and antibacterial activities, including liver fibrosis and many tumors; however, no study has demonstrated its effect on lipopolysaccharide- (LPS-) induced renal inflammation. To investigate the anti-inflammatory effects of oridonin on human renal proximal tubular epithelial cells (HK-2 cells), the expression levels of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS) were evaluated by Western blot analysis and 2′,7′-dichlorofluorescein diacetate (DCF-DA) staining, respectively. The level of intracellular ROS increased in a dose-dependent manner following LPS treatment, whereas oridonin inhibited this effect, suggestive of its ability to prevent ROS accumulation. As the mitogen-activated protein kinase (MAPK) family of enzymes plays an important role in physiological responses, we examined the activation of JNK by Western blotting and found that oridonin attenuated LPS-induced JNK phosphorylation. Oridonin also attenuated RAW 264.7 cell chemotaxis towards LPS-treated HK-2 cells. Taken together, oridonin protected against LPS-induced inflammation including ROS accumulation, JNK activation, NF-κB nuclear translocation in HK-2 cells, and functionally blocked macrophage chemotaxis towards LPS-treated HK-2 cells. Oridonin may exhibit therapeutic potential by the anti-inflammation effect in LPS-treated HK-2 cells.
Highlights
Chronic kidney disease (CKD) is characterized by a progressive and irreversible exacerbation of the renal excretory function that necessitates renal replacement therapy in the form of dialysis or renal transplants and may lead to death [1]. erefore, chronic kidney disease (CKD) is a global health problem with serious implications
To investigate the inflammatory effect of LPS on HK-2 cells, we evaluated Jun N-terminal kinase (JNK) phosphorylated and NF-κB nuclear translocation by Western blot analysis. e result obtained indicated that LPS-induced JNK phosphorylation (JNK pathway activation) without alerting in the total JNK protein levels (Figures 2(a) and 2(b)) and induced the nuclear translocation of NF-κB p65 (Figure 3, lane 6)
We evaluated the effects of oridonin on LPS-induced reactive oxygen species (ROS) production, JNK phosphorylation, NF-κB nuclear translocation in HK-2 cells, and RAW 264.7 chemotaxis. e results obtained indicated that oridonin treatment attenuated LPSinduced ROS production (Figure 5, column 3, 4), JNK phosphorylation (Figure 6, lanes 2, 4), and nuclear translocation of NF-κB p65 (Figure 3, lanes 6, 8)
Summary
Chronic kidney disease (CKD) is characterized by a progressive and irreversible exacerbation of the renal excretory function that necessitates renal replacement therapy in the form of dialysis or renal transplants and may lead to death [1]. erefore, CKD is a global health problem with serious implications. Renal tubulointerstitial inflammation has an important role in fibrosis, which is the key pathogenetic alteration associated with CKD [2]. Wang et al suggested that an increase in oxidative stress plays a critical role in mediating metabolic syndrome-induced tubulointerstitial injury [3]. Albuminuria may serve as an endogenous danger-associated molecular pattern (DAMP) that stimulates tubulointerstitial inflammation via mitochondrial reactive oxygen species- (mtROS-) mediated activation of the cytoplasmic Nlrp inflammasome in HK-2 cells [4]. Evidence indicates that SIRT3, an antiaging molecule regulated by calorie restriction and mitochondrionlocalized NAD (+) -dependent deacetylase, positively regulates both mitochondrial oxidative capacity and antioxidant gene expression, thereby reducing ROS accumulation in mouse proximal tubular cells [5]. It is well known that activated macrophages respond to inflammation induced by bacterial lipopolysaccharide (LPS) by producing cytokines
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