Calcium oxalate crystals induces tight junction disruption in distal renal tubular epithelial cells by activating ROS/Akt/p38 MAPK signaling pathway

Abstract

Tight junction plays important roles in regulating paracellular transports and maintaining cell polarity. Calcium oxalate monohydrate (COM) crystals, the major crystalline composition of kidney stones, have been demonstrated to be able to cause tight junction disruption to accelerate renal cell injury. However, the cellular signaling involved in COM crystal-induced tight junction disruption remains largely to be investigated. In the present study, we proved that COM crystals induced tight junction disruption by activating ROS/Akt/p38 MAPK pathway. Treating Madin–Darby canine kidney (MDCK) cells with COM crystals induced a substantial increasing of ROS generation and activation of Akt that triggered subsequential activation of ASK1 and p38 mitogen-activated protein kinase (MAPK). Western blot revealed a significantly decreased expression of ZO-1 and occludin, two important structural proteins of tight junction. Besides, redistribution and dissociation of ZO-1 were observed by COM crystals treatment. Inhibition of ROS by N-acetyl-l-cysteine (NAC) attenuated the activation of Akt, ASK1, p38 MAPK, and down-regulation of ZO-1 and occludin. The redistribution and dissociation of ZO-1 were also alleviated by NAC treatment. These results indicated that ROS were involved in the regulation of tight junction disruption induced by COM crystals. In addition, the down-regulation of ZO-1 and occludin, the phosphorylation of ASK1 and p38 MAPK were also attenuated by MK-2206, an inhibitor of Akt kinase, implying Akt was involved in the disruption of tight junction upstream of p38 MAPK. Thus, these results suggested that ROS-Akt-p38 MAPK signaling pathway was activated in COM crystal-induced disruption of tight junction in MDCK cells.

β1 Integrin regulates adult lung alveolar epithelial cell inflammation

“…In addition, claudin-18-null mice develop AEC hyperplasia and macrophage accumulation over time (89)(90)(91). Although a causal relationship between β 1 integrin and claudins has not been described, previous in vitro studies demonstrated that ROS can disrupt tight junctions (92)(93)(94), suggesting that β 1 integrin-mediated ROS could regulate tight junctions via effects on claudin expression. Another phenotype identified in β1 rtTA mice is AEC proliferation.…”

Atorvastatin inhibits renal inflammatory response induced by calcium oxalate crystals via inhibiting the activation of TLR4/NF‐κB and NLRP3 inflammasome

“…Consistent with our previous results, CaOx crystals significantly increased the secretion of LDH, the adherent and endocytosis of CaOx crystals in HK-2 cells, and increased the levels of CRE and BUN in rat serum and the deposition of crystals in rat kidney. 20,22 Yu et al 23 reported that CaOx crystals increased the production of ROS and induced the damage to HK-2 cells via mediating the AKT/P38/MAPK pathway. The above data indicated that oxidative stress played a critical role in cell damage and intrarenal crystal formation.…”

Icariin and its phosphorylated derivatives alleviate intestinal epithelial barrier disruption caused by enterotoxigenic Escherichia coli through modulate p38 MAPK in vivo and in vitro

“…Pretreatment with ICA and pICA significantly attenuated ETEC K88-induced pro-inflammatory cytokines expression in jejunum of piglets and IPEC-J2 cells. 47 On the other hand, the p38 signaling pathway indirectly disrupts the intestinal epithelial barrier function by regulating the progression of inflammation and oxidative stress in intestinal epithelial cells. 42 Under physiological conditions, some intermediates produced during oxidative phosphorylation, such as ROS, are important signaling molecules that regulate cellular biochemical processes.…”

“…On the one hand, the p38 signaling pathway is directly involved in the destruction of the intestinal epithelial TJ proteins ZO-1 and Occludin, while the expression of TJ protein returns to normal after inhibition of the p38 signaling pathway. 47 On the other hand, the p38 signaling pathway indirectly disrupts the intestinal epithelial barrier function by regulating the progression of inflammation and oxidative stress in intestinal epithelial cells. 48,49 In the current study, our data revealed that ETEC K88 challenge significantly increased p38 MAPK gene expression and phosphorylated p38 MAPK protein expression, while ICA and pICA pretreatment effectively reversed these changed.…”