Jeney, ViktóriaAbabneh, Haneen2024-06-262024-06-262024https://hdl.handle.net/2437/375064Ectopic calcification, particularly vascular calcification and cataract formation are significant health concerns associated with ageing, diabetes, and CKD. Pathological osteo-/chondrogenic transdifferentiation contributes to ectopic calcification, particularly in vascular smooth muscle cells and valve interstitial cells. Studies have indicated an association between osteo- /chondrogenic transdifferentiation and ectopic calcification in both VC and cataract formation with common etiological factors. Type 2 diabetes is associated with a higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia. Hydroxyapatite deposition is present in cataractous lenses and can result from osteo-/chondrogenic transdifferentiation and calcification of the lens epithelial cells. In this study, we investigated the possibility that hyperglycaemia promotes osteo- /chondrogenic transdifferentiation of HuLECs, and we studied whether CKD triggered cardiac tissue calcification. We determined that high glucose levels increased the expression of OMinduced osteo-/chondrogenic markers Runx2, Sox9, ALP, and OCN, and nuclear translocation of Runx2. High glucose-induced calcification was attenuated in Runx2‐deficient HuLECs. Additionally, high glucose levels stabilised the regulatory alpha subunits of hypoxia‐inducible factor 1 (HIF‐1), triggered nuclear translocation of HIF‐1α, and increased the expression of HIF‐1 target genes. Gene silencing of HIF‐1α or HIF‐2α attenuated high glucose‐induced calcification of HuLECs, whereas hypoxia mimetics enhanced the calcification of HuLECs under normal glucose conditions. We have developed a CKD mouse model using adenine and a high-phosphate-containing diet. Serum urea, creatinine, and phosphate levels were elevated thus confirming the success of the diet. This diet led to the calcification of CKD mouse hearts which was visualised using the OsteoSenseTM dye. In addition, we found that the hearts of CKD mice expressed the hypoxia markers HIF-1α and HIF-2α, and the osteo-/chondrogenic markers Sox9 and Runx2. In conclusion, our studies shed light on the importance of HIF-1 pathway activation in soft tissue calcification, which may be relevant in diabetes-induced cataract formation and CKDassociated valve calcification.69enchronic kidney disease, diabetes, lens calcification, hypoxia, valve calcificationElméleti orvostudományokOrvostudományok