CAV1 unveils a novel therapeutic target for nephrolithiasis by modulating CaSR and ER stress

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Nephrolithiasis (kidney stones) involves complex crystal-cell interactions.
• Endoplasmic reticulum (ER) stress is implicated, but its mechanism in kidney stone formation is unclear.
• Calcium oxalate monohydrate (COM) crystals are a common cause of kidney stones.

Purpose of the Study:

• To elucidate the mechanism of ER stress in COM crystal-induced kidney stone formation.
• To investigate the role of calcium-sensing receptor (CaSR) and caveolin-1 (CAV1) in this process.
• To identify potential therapeutic targets for nephrolithiasis.

Main Methods:

• Utilized HK-2 renal tubular epithelial cells and in vivo models.
• Investigated the effects of COM crystals on intracellular Ca2+, CaSR expression, and ER stress.
• Analyzed protein-protein interaction networks from GWAS and microarray data.
• Examined the role of CAV1, epidermal growth factor receptor (EGFR), and AKT signaling.
• Used CaSR inhibitor NPS2390, CAV1 overexpression, and proteasome inhibitor MG-132.

Main Results:

• COM crystals increased intracellular Ca2+ and CaSR expression, inducing ER stress in HK-2 cells.
• CAV1, EGFR, and the focal adhesion pathway emerged as key intersection points in network analysis.
• COM exposure decreased CAV1 protein levels and impaired the EGFR-AKT pathway, leading to HK-2 cell apoptosis.
• CAV1 overexpression reversed COM-induced apoptosis, ER stress, and CaSR upregulation.
• Proteasome inhibition prevented CAV1 downregulation, indicating post-translational regulation.

Conclusions:

• CAV1 plays a protective role against COM crystal-induced kidney stone formation.
• CAV1 modulates CaSR expression and ER stress, offering a potential therapeutic strategy.
• Targeting CAV1 may be a promising approach for nephrolithiasis treatment.