RRC ID 82718
Author Kawase K, Hamamoto S, Unno R, Taguchi K, Okada A, Yasui T.
Title Prolyl hydroxylase domain inhibitors prevent kidney crystal formation by suppressing inflammation.
Journal Urolithiasis
Abstract The early stages of kidney crystal formation involve inflammation and hypoxia-induced cell injury; however, the role of the hypoxic response in kidney crystal formation remains unclear. This study investigated the effects of a prolyl hydroxylase domain inhibitor (roxadustat) on renal calcium oxalate (CaOx) crystal formation through in vitro and in vivo approaches. In the in vitro experiment, murine renal tubular cells (RTCs) were exposed to varying roxadustat concentrations and CaOx crystals. CaOx monohydrate (COM) crystal adhesion was evaluated using fluorescent labels, whereas western blotting was used to examine protein expression. Quantitative real-time polymerase chain reaction was used to analyze gene expression changes. Macrophage responses were investigated by co-culturing them with RTCs treated with COM. In the in vivo experiment, C57BL/6J mice were injected with roxadustat or saline for 2 days, followed by glyoxylate for 6 days to induce renal crystal deposition. Biochemical measurements recorded plasma erythropoietin, urinary data, and pH levels. Roxadustat suppressed the adhesion of COM crystals to RTCs and the expression of proinflammatory genes, such as chemokine (C-C motif) ligand 2 (Ccl2) and secreted phosphoprotein 1 (Spp1). Roxadustat decreased the expression levels of Ccl2, tumor necrosis factor (Tnf), and interleukin 6 (Il6) in co-cultured macrophages. In the in vivo experiment, the amount of renal CaOx crystal deposits was significantly lower in the roxadustat-treated group than in the vehicle group. Roxadustat treatment decreased Ccl2, Tnf, and adheision G protein-coupled receptor E1 (Adgre1) expression in the kidneys. Roxadustat reduced kidney inflammation and CaOx crystal deposition, suggesting its potential as a therapeutic option for kidney stone prevention.
Volume 53(1)
Pages 16
Published 2024-12-26
DOI 10.1007/s00240-024-01677-x
PII 10.1007/s00240-024-01677-x
PMID 39724472
MeSH Animals Calcium Oxalate* Cells, Cultured Crystallization* Glycine / analogs & derivatives Glycine / pharmacology Glycine / therapeutic use Inflammation / prevention & control Isoquinolines / pharmacology Isoquinolines / therapeutic use Kidney Calculi* / prevention & control Kidney Tubules / cytology Kidney Tubules / drug effects Kidney Tubules / pathology Macrophages / drug effects Macrophages / metabolism Male Mice Mice, Inbred C57BL* Prolyl-Hydroxylase Inhibitors* / pharmacology Prolyl-Hydroxylase Inhibitors* / therapeutic use
Resource
Human and Animal Cells RAW 264(RCB0535)