The significance of reactive oxygen species in the formation of calcium oxalate stones and the protective effects of antioxidants on the kidneys

Abstract

Exposure of renal tubular epithelial cells (RTCs) to kidney stones or calcium oxide crystals triggers the production of reactive oxygen species (ROS), leading to oxidative stress. This oxidative milieu incites cellular injury and elicits an inflammatory cascade within the RTCs. Notably, the cellular membranes of the compromised cells facilitate the adherence and subsequent retention of crystals, which is instrumental in the pathogenesis of kidney stones. The pathways of ROS production are diverse, involving numerous signaling cascades. Recent researchers' endeavors have elucidated that selective antioxidants can attenuate intracellular ROS concentrations by modulating these intricate signaling cascades. This reduction in ROS levels has been empirically demonstrated to significantly curtail the accumulation of calcium oxalate crystals within renal tissues in animal models, heralding a novel therapeutic paradigm for the amelioration of nephrolithiasis. In this review, we endeavor to elucidate the contributory role of ROS in kidney stone and explore the protective mechanisms by which certain antioxidants safeguard renal function.

Keywords: antioxidants; kidney stones; oxidative stress; reactive oxygen species; renal.

Figure 1

Production of reactive oxygen species (ROS). The generation of reactive oxygen species (ROS) primarily originates from the oxidative respiratory chains within mitochondria. Alterations in the internal environment, such as a decrease in the level of oxygen, mitochondrial membrane potential, or mitochondrial function, trigger reverse electron transfer (RET), facilitating electron circulation between C I and C II. Ultimately, this process culminates in the reaction of electrons with oxygen and subsequent ROS production.

Figure 2

Exposure to oxalate and/or calcium oxalate crystals triggers renal tubular epithelial cells to produce excess reactive oxygen species (ROS), leading to oxidative stress (OS) and inflammatory responses. This process is driven by several molecular mechanisms: (A) Activation of the NLRP3 inflammasome releases inflammatory factors, worsening tubular epithelial damage. (B) Elevated ROS levels upregulate MMP-9 expression, increasing crystal adherence.

Figure 3

Under normal physiological conditions, the Keap1 complex binds to Nrf2, promoting its ubiquitination and subsequent degradation by the 26S proteasome. However, oxidative stress alters specific cysteine residues in Keap1, causing a conformational change that disrupts Nrf2 ubiquitination. This allows Nrf2 to translocate to the nucleus and bind to the antioxidant response element (ARE) of target genes via heterodimerization with sMAF protein, inducing the expression of cellular protective genes.