Abstract
Oxidative stress and inflammatory response are closely related to nephrolithiasis. This study is aimed at exploring whether rosiglitazone (ROSI), a regulator of macrophage (Mp) polarization, could reduce renal calcium oxalate (CaOx) deposition by ameliorating oxidative stress and inflammatory response. Male C57 mice were equally and randomly divided into 7 groups. Kidney sections were collected on day 5 or day 8 after treatment. Pizzolato staining and polarized light optical microscopy were used to detect crystal deposition. PAS staining and TUNEL assay were performed to assess the tubular injury and cell apoptosis, respectively. Gene expression was assessed by immunohistochemistry, immunofluorescence, ELISA, qRT-PCR, and Western blot. The reactive oxygen species (ROS) level was assessed using a fluorescence microplate and fluorescence microscope. Hydrogen peroxide (H2O2), malonaldehyde (MDA), and glutathione (GSH) were evaluated to determine oxidative stress. Lactic dehydrogenase (LDH) activity was examined to detect cell injury. Adhesion of CaOx monohydrate (COM) crystals to HK-2 cells was detected by crystal adhesion assay. HK-2 cell death or renal macrophage polarization was assessed by flow cytometry. In vivo, renal crystal deposition, tubular injury, crystal adhesion, cell apoptosis, oxidative stress, and inflammatory response were significantly increased in the 7-day glyoxylic acid- (Gly-) treated group but were decreased in the ROSI-treated groups, especially in the groups pretreated with ROSI. Moreover, ROSI significantly reduced renal Mp aggregation and M1Mp polarization but significantly enhanced renal M2Mp polarization. In vitro, ROSI significantly suppressed renal injury, apoptosis, and crystal adhesion of HK-2 cells and markedly shifted COM-stimulated M1Mps to M2Mps, presenting an anti-inflammatory effect. Furthermore, ROSI significantly suppressed oxidative stress by promoting the Nrf2/HO-1 pathway in HK-2 cells. These findings indicate that ROSI could ameliorate renal tubular injury that resulted from oxidative stress and inflammatory response by suppressing M1Mp polarization and promoting M2Mp polarization. Therefore, ROSI is a potential therapeutic and preventive drug for CaOx nephrolithiasis.
Highlights
Urolithiasis has a reported prevalence of 10% and 50% recurrence rates [1], potentially resulting in chronic kidney disease or even renal failure [2]
This study revealed that ROSI could suppress crystal deposition in the kidney of hyperoxaluric mice by inhibiting oxidative stress and inflammatory response
The results revealed that crystals were mainly deposited in renal tubules at the corticomedullary borders and the number of crystals gradually increased over time in the Glyoxylic acid (Gly) groups (Figures 1(a) and 1(b))
Summary
Urolithiasis has a reported prevalence of 10% and 50% recurrence rates [1], potentially resulting in chronic kidney disease or even renal failure [2]. In the process of calcium oxalate (CaOx) crystal deposition, injury to the tubular epitheliums [4], which is frequently mediated by oxidative stress, plays a critical role during CaOx crystal deposition [5]. CaOx crystals upregulate NADPH oxidase p47phox and lead to overproduction of reactive oxygen species (ROS) in the tubular epitheliums. This is further enhanced by the proinflammatory effect of macrophages [6]. ROS are the leading mediators of oxidative stress injury, damaging the mitochondrial membrane and reducing the transmembrane potential [7, 8]. CaOx crystalinduced oxidative stress is a critical process for nephrolithiasis formation
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