Clinical and Genetic Associations of Vascular Calcification and Renal Papillary Microcalcification in Kidney Stone Formation: Mechanisms and Therapeutic Implications of the IL-17 Pathway

Purpose: This study aimed to investigate the association between vascular calcification, renal papillary microcalcification, and kidney stone formation, focusing on elucidating the role of the IL-17 signaling pathway and evaluating the therapeutic potential of triptolide. Patients and methods: A Chinese cohort of 163 kidney stone patients and 168 controls underwent unenhanced CT to measure renal papillary attenuation values and abdominal aortic calcification index (ACI). Bioinformatics analysis identified common differentially expressed genes (DEGs) in nephrolithiasis (GSE73680) and atherosclerosis (GSE100927) datasets. In vitro (calcium-treated HK-2 cells) and in vivo (rat ethylene glycol-induced urolithiasis) models validated IL-17 pathway mechanisms and triptolide efficacy. Results: Stone formers exhibited significantly higher renal papillary CT attenuation values (54.66 vs. 47.37 HU, p<0.0001) correlating with ACI (R²=0.8275, p<0.001). Bioinformatics analysis identified 25 common DEGs, with upregulated genes enriched in the IL-17 pathway. Calcium-stressed HK-2 cells exhibited IL-17-dependent overexpression of MMP1/CCL7, which was reversed by triptolide, (NF-κB inhibitor). In rats, triptolide (1.2–2.4 mg/kg) reduced renal injury markers (VCAM-1/ICAM-1/KIM-1), suppressed osteopontin (p<0.01), and attenuated stone formation. Conclusion: Elevated renal papillary CT attenuation values predict stone risk and correlate with aortic calcification. The IL-17 pathway drives stone formation via MMP1/CCL7, and triptolide inhibits this cascade, thereby offering a novel therapeutic strategy.