Role of ROS-Induced NLRP3 Inflammasome Activation in the Formation of Calcium Oxalate Nephrolithiasis

Abstract

Calcium oxalate nephrolithiasis is a common and highly recurrent disease in urology; however, its precise pathogenesis is still unknown. Recent research has shown that renal inflammatory injury as a result of the cell-crystal reaction plays a crucial role in the development of calcium oxalate kidney stones. An increasing amount of research have confirmed that inflammation mediated by the cell-crystal reaction can lead to inflammatory injury of renal cells, promote the intracellular expression of NADPH oxidase, induce extensive production of reactive oxygen species, activate NLRP3 inflammasome, discharge a great number of inflammatory factors, trigger inflammatory cascading reactions, promote the aggregation, nucleation and growth process of calcium salt crystals, and ultimately lead to the development of intrarenal crystals and even stones. The renal tubular epithelial cells (RTECs)-crystal reaction, macrophage-crystal reaction, calcifying nanoparticles, endoplasmic reticulum stress, autophagy activation, and other regulatory factors and mechanisms are involved in this process.

Keywords: autophagy; endoplasmic reticulum stress; inflammasome; macrophage; nanoparticles; reactive oxygen species.

Figure 1

Possible mechanism and regulation of ROS-induced NLRP3 inflammasome activation in the formation of calcium oxalate nephrolithiasis. The secretion of mature forms of IL-1β and IL-18 is the result of NLRP3 inflammasome activation. These mediators have the properties of pro-inflammatory activation, which in turn promote the adhesion, aggregation and growth of crystals. The interaction of crystals or nanoparticles with cells can cause mitochondrial damage and increased NADPH oxidase activity, and then generate ROS, which mediates NLRP3 inflammasome transcription and activation through the ROS-dependent of NF-κB and autophagy signaling pathway. ER induces ROS production via NOX4 and ERO1 during stress. The release of Ca2+in the ER causes mitochondrial damage which further aggravates the release of ROS. High concentration of ROS can induce excessive activation of autophagy, thereby stimulate the inflammasomes to release a great number of inflammatory factors. The activation of NLRP3 inflammasome may further increase the level of autophagy, resulting in an inflammatory chain reaction.