KUO-HOW HUANGGuan, Siao-SyunSiao-SyunGuanLin, Wei-HanWei-HanLinWu, Cheng-TienCheng-TienWuSheu, Meei-LingMeei-LingSheuChiang, Chih-KangChih-KangChiangLiu, Shing-HwaShing-HwaLiu2023-12-072023-12-072019-06-302073-4409https://scholars.lib.ntu.edu.tw/handle/123456789/637604Diabetes-associated advanced glycation end-products (AGEs) can increase extracellular matrix (ECM) expression and induce renal fibrosis. Calbindin-D28k, which plays a role in calcium reabsorption in renal distal convoluted tubules, is increased in a diabetic kidney. The role of calbindin-D28k in diabetic nephropathy still remains unclear. Here, calbindin-D28k protein expression was unexpectedly induced in the renal tubules of db/db diabetic mice. AGEs induced the calbindin-D28k expression in human renal proximal tubule cells (HK2), but not in mesangial cells. AGEs induced the expression of fibrotic molecules, ECM proteins, epithelial-mesenchymal transition (EMT) markers, and endoplasmic reticulum (ER) stress-related molecules in HK2 cells, which could be inhibited by a receptor for AGE (RAGE) neutralizing antibody. Calbindin-D28k knockdown by siRNA transfection reduced the cell viability and obviously enhanced the protein expressions of fibrotic factors, EMT markers, and ER stress-related molecules in AGEs-treated HK2 cells. Chemical chaperone 4-Phenylbutyric acid counteracted the AGEs-induced ER stress and ECM and EMT markers expressions. Calbindin-D28k siRNA in vivo delivery could enhance renal fibrosis in db/db diabetic mice. These findings suggest that inducible calbindin-D28k protects against AGEs/RAGE axis-induced ER stress-activated ECM induction and cell injury in renal proximal tubule cells.enadvanced glycation end products; calbindin-D28k; diabetic nephropathy; renal fibrosis; renal proximal tubule[SDGs]SDG3journal article10.3390/cells8070660312620602-s2.0-85089578237https://api.elsevier.com/content/abstract/scopus_id/85089578237