Tight junction and kidney stone disease

Defects of tight junction (TJ) are involved in many diseases related to epithelial cell functions, including kidney stone disease (KSD), which is a common disease affecting humans for over a thousand years. This review provides brief overviews of KSD and TJ, and summarizes the knowledge on crystal-induced defects of TJ in renal tubular epithelial cells (RTECs) in KSD. Calcium oxalate (CaOx) crystals, particularly COM, disrupt TJ via p38 MAPK and ROS/Akt/p38 MAPK signaling pathways, filamentous actin (F-actin) reorganization and α-tubulin relocalization. Stabilizing p38 MAPK signaling, reactive oxygen species (ROS) production, F-actin and α-tubulin by using SB239063, N-acetyl-L-cysteine (NAC), phalloidin and docetaxel, respectively, successfully prevent the COM-induced TJ disruption and malfunction. Additionally, genetic disorders of renal TJ, including mutations and single nucleotide polymorphisms (SNPs) of CLDN2, CLDN10b, CLDN14, CLDN16 and CLDN19, also affect KSD. Finally, the role of TJ as a potential target for KSD therapeutics and prevention is also discussed.

 

Comments:

The passage you provided highlights the significance of tight junctions (TJ) in various diseases related to epithelial cell functions, with a specific focus on kidney stone disease (KSD). KSD has been a prevalent human affliction for centuries, and understanding the molecular mechanisms involving TJ defects, particularly in renal tubular epithelial cells (RTECs), is crucial.

In the context of KSD, calcium oxalate (CaOx) crystals, especially COM (calcium oxalate monohydrate), disrupt TJ integrity through multiple pathways. These disruptions involve the activation of p38 MAPK (mitogen-activated protein kinase) and ROS/Akt/p38 MAPK signaling pathways, reorganization of filamentous actin (F-actin), and relocalization of α-tubulin. The disruption of TJ can be mitigated by stabilizing p38 MAPK signaling, reducing reactive oxygen species (ROS) production, and maintaining the structural integrity of F-actin and α-tubulin. Specifically, using compounds like SB239063 (a p38 MAPK inhibitor), N-acetyl-L-cysteine (NAC, an antioxidant), phalloidin (a stabilizer of F-actin), and docetaxel (a stabilizer of microtubules, which includes α-tubulin) can prevent the TJ disruption induced by COM crystals in RTECs.

Moreover, genetic factors also play a role in KSD, with mutations and single nucleotide polymorphisms (SNPs) in genes related to renal TJ (such as CLDN2, CLDN10b, CLDN14, CLDN16, and CLDN19) contributing to the disease.

The passage concludes by suggesting that understanding TJ disruptions in diseases like KSD opens avenues for potential therapeutic strategies and preventive measures. Targeting TJ function could be a promising approach in the development of treatments for KSD.

Related Products

Cat.No.	Product Name	Information
S7741	SB239063	SB239063 is a potent and selective p38 MAPKα/β inhibitor with IC50 of 44 nM, showing no activity against the γ- and δ-kinase isoforms.

Related Targets

p38 MAPK