Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes.
BACKGROUND
Activations of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported.


METHODS
We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of ER stress and its protective effect on advanced glycation end products (AGEs)-induced apoptosis in murine podocytes. Podocytes were incubated with increasing doses of AGEs for variable time periods. Apoptosis was quantitatively determined by flow cytometry detecting propidium iodide expression and annexin V binding simultaneously. Level of glucose-regulated protein 78 (ER stress marker) expression was determined by Western blot. Intracellular calcium concentration ([Ca(2+)](i)) was recorded by a laser confocal microscope and the Ca(2+) indicator Fluo-3 labeling.


RESULTS
AGEs induced podocyte apoptosis and increased the expression of glucose-regulated protein 78 in a dose- and time-dependent manner as compared with bovine serum albumin. These changes were accompanied by a rapid rise in [Ca(2+)](i) of podocytes. TUDCA was capable of abolishing AGEs-induced expression of glucose-regulated protein 78 and subsequently inhibited apoptosis in a dose-dependent manner.


CONCLUSIONS
We propose that ER stress plays an important role in AGEs-induced apoptosis and that TUDCA prevents apoptosis by blocking an ER stress-mediated apoptotic pathway. This novel mechanism of TUDCA action suggests new intervention methods for AGEs-induced apoptosis of mouse podocytes in diabetic nephropathy.
Chen
Yu
Y
Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
Liu
Cui Ping
CP
Xu
Kuan Feng
KF
Mao
Xiao Dong
XD
Lu
Yi Bing
YB
Fang
Li
L
Yang
Jun Wei
JW
Liu
Chao
C
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D013654:Taurine / Q000378:metabolism*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D013997:Time Factors; D014580:Ursodeoxycholic Acid / Q000737:chemistry*
D000091342:Endoplasmic Reticulum Chaperone BiP; D017127:Glycation End Products, Advanced; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D013654:Taurine; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D014580:Ursodeoxycholic Acid; D002118:Calcium