CAV1 alleviated CaOx stones formation via suppressing autophagy-dependent ferroptosis

Abstract

Background Calcium oxalate (CaOx) is the most common type of kidney stone, but the mechanism of CaOx stones formation remains unclear. The injury of renal cells such as ferroptosis and autophagy has been considered a basis for stones formation. Methods We conducted transmission electron microscope (TEM), reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and C11-BODIPY analysis to explore whether CaOx could induce autophagy-dependent ferroptosis in vivo and in vitro . To explore the possible mechanism, we conducted bioinformatic analysis of patients with or without CaOx stones, Western blot and qPCR were used to identify the different genes we found in bioinformatic analysis. Results In our study, we found that CaOx could induce autophagy-dependent ferroptosis no matter in vivo or in vitro , which might finally lead to urolithiasis. Bioinformatic analysis of the dataset indicated that the expression of caveolin-1 (CAV1) was higher in control patients than CaOx stone patients, the STRING database indicated that CAV1 might interact with low density lipoprotein receptro-related protein 6 (LRP6), Gene Set Enrichment Analysis (GSEA) showed that the WNT pathway positively associated with the control group while negatively related to the stone group, and LRP6 was the core gene of the WNT pathway. Western blot found that CAV1, LRP6, and Wnt/β-Catenin were decreased in Human Kidney2 (HK2) cells stimulated with CaOx. Furthermore, the WNT pathway was considered to be involved in autophagy and ferroptosis. Conclusions We presumed that CAV1 could ameliorate autophagy-dependent ferroptosis through the LRP6/Wnt/β-Catenin axis, and finally alleviate CaOx stone formation.

Ferroptosis and its emerging role in kidney stone formation

“…In recent years, with the progressive understanding of ferroptosis, several studies have demonstrated a correlation between ferroptosis and kidney stones. Yang et al [ 55 ] established a rat kidney stone model by injecting glyoxalate and found that the mitochondria in rat RTECs became smaller and increased in membrane density, and the mitochondria were severely damaged. The change of mitochondrial ultrastructure was the morphological characteristic of ferroptosis in the cells, which proved that ferroptosis was involved in the formation of kidney stones.…”

Novel Insight into Ferroptosis in Kidney Diseases

“…Additionally, knockdown of NCOA4 alleviated the effects of oxalate on ferroptosis in HK-2 cells [111]. Another study demonstrated that CAV1 reduced CaOx stone formation by blocking autophagy-dependent ferroptosis [112]. CaOx was discovered to trigger autophagy-dependent ferroptosis in both in vivo and in vitro settings, which may contribute to the development of urolithiasis [112].…”

“…Another study demonstrated that CAV1 reduced CaOx stone formation by blocking autophagy-dependent ferroptosis [112]. CaOx was discovered to trigger autophagy-dependent ferroptosis in both in vivo and in vitro settings, which may contribute to the development of urolithiasis [112]. GSEA revealed that the WNT pathway was negatively associated with the stone group, and lipoprotein receptor-related protein 6 (LRP6) was the core gene of the WNT pathway [112].…”

“…CaOx was discovered to trigger autophagy-dependent ferroptosis in both in vivo and in vitro settings, which may contribute to the development of urolithiasis [112]. GSEA revealed that the WNT pathway was negatively associated with the stone group, and lipoprotein receptor-related protein 6 (LRP6) was the core gene of the WNT pathway [112]. Furthermore, the STRING database revealed that CAV1 might interact with LRP6 [112].…”

“…GSEA revealed that the WNT pathway was negatively associated with the stone group, and lipoprotein receptor-related protein 6 (LRP6) was the core gene of the WNT pathway [112]. Furthermore, the STRING database revealed that CAV1 might interact with LRP6 [112]. Finally, CAV1 was shown to reduce CaOx stone formation by enhancing autophagy-dependent ferroptosis via the LRP6/Wnt/-Catenin axis [113].…”