Nephrolithiasis is a complex disease resulted from abnormal crystal deposition in renal tissues. The crystal-cell interaction represents a critical step in kidney stone formation, involving numerous genes and proteins. We previously identified endoplasmic reticulum (ER) stress as a key biological process in the crystal-cell interactions, the precise mechanism of which has remained unclear. In the present study, we found that calcium oxalate monohydrate (COM) crystals induced an overload of intracellular Ca2+ and an upregulation of calcium-sensing receptor (CaSR) expression in the renal tubular epithelial cells HK-2, both of which were reversed by the CaSR inhibitor NPS2390 that also mitigated the COM-induced ER stress. The protein-protein interaction (PPI) network analysis of the genome-wide association studies (GWAS) data and the microarray data from kidney stone patients revealed that caveolin-1 (CAV1), epidermal growth factor receptor (EGFR), and the focal adhesion pathway formed a crucial intersection within the interactional networks. COM exposure induced HK-2 apoptosis, accompanied by a decrease in CAV1 protein levels and damage to EGFR-AKT signaling pathway, which was reversed by CAV1 overexpression. COM did not significantly affect CAV1 mRNA levels. Treatment with the proteasome inhibitor MG-132 prevented the downregulation of CAV1. CAV1 overexpression also inhibited ER stress and the upregulation of CaSR induced by COM. Similar results were observed in in vivo experiments. In conclusion, the present study suggests that CAV1 may be a promising target for nephrolithiasis therapy by modulating CaSR and ER stress.
Biochimica et biophysica acta. Molecular basis of disease. 2025 Feb 28 [Epub ahead of print]
Yang Li, Baoyu Yang, Haozhen Wang, Wenqi Hu, Ting Liu, Xiuli Lu, Bing Gao
Department of Cell Biology and Genetics, Shenyang Medical College, 146 Huanghe North Street, Shenyang 110034, China; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang 110034, China., Department of Biochemistry and Cell Biology, School of Life Science, Liaoning University, Shenyang 110036, China., Department of Biochemistry and Cell Biology, School of Life Science, Liaoning University, Shenyang 110036, China. Electronic address: ., Department of Cell Biology and Genetics, Shenyang Medical College, 146 Huanghe North Street, Shenyang 110034, China; Key Laboratory of Renal Calcification Disease Prevention and Treatment, 146 Huanghe North Street, Shenyang 110034, China. Electronic address: .