TY - JOUR
T1 - Induction of diabetes in aged C57B6 mice results in severe nephropathy
T2 - An association with oxidative stress, endoplasmic reticulum stress, and inflammation
AU - Wu, Jin
AU - Zhang, Ruihua
AU - Torreggiani, Massimo
AU - Ting, Adrian
AU - Xiong, Huabao
AU - Striker, Gary E.
AU - Vlassara, Helen
AU - Zheng, Feng
PY - 2010/5
Y1 - 2010/5
N2 - Kidney aging is a slowly progressive process that is postulated to be accelerated by intervening diseases, such as diabetes, due in part to the addition of excessive stress and inflammation from the intervening disease to the underlying aging process. This hypothesis was tested by inducing diabetes with streptozotocin in 18-month-old, aging mice. After 4 months of diabetes, these mice developed severe albuminuria, elevated creatinine levels, and renal lesions including extensive apoptotic cell death, glomerulosclerosis, afferent and efferent hyalinosis, and tubulointerstitial inflammation and fibrosis. These symptoms were associated with elevated oxidative stress. The presence of endoplasmic reticulum (ER) stress in 22-month-old diabetic kidneys resulted in up-regulation of C/EBP homologous protein (CHOP), which may play a role in increasing kidney lesions because CHOP-deficient proximal tubular cells were resistant to ER stress-induced cell death, and CHOP-deficient mice were protected from diabetic nephropathy. Moreover, CHOP-deficient mice did not develop albuminuria as they aged. Inflammation, another key component of progressive diabetic nephropathy, was prominent in 22-month-old diabetic kidneys. The expression of tumor-necrosis factor-α in 22-month-old diabetic kidneys may play a role in inflammation, ER stress, and apoptosis. Thus, diabetes may accelerate the underlying kidney aging process present in old mice.
AB - Kidney aging is a slowly progressive process that is postulated to be accelerated by intervening diseases, such as diabetes, due in part to the addition of excessive stress and inflammation from the intervening disease to the underlying aging process. This hypothesis was tested by inducing diabetes with streptozotocin in 18-month-old, aging mice. After 4 months of diabetes, these mice developed severe albuminuria, elevated creatinine levels, and renal lesions including extensive apoptotic cell death, glomerulosclerosis, afferent and efferent hyalinosis, and tubulointerstitial inflammation and fibrosis. These symptoms were associated with elevated oxidative stress. The presence of endoplasmic reticulum (ER) stress in 22-month-old diabetic kidneys resulted in up-regulation of C/EBP homologous protein (CHOP), which may play a role in increasing kidney lesions because CHOP-deficient proximal tubular cells were resistant to ER stress-induced cell death, and CHOP-deficient mice were protected from diabetic nephropathy. Moreover, CHOP-deficient mice did not develop albuminuria as they aged. Inflammation, another key component of progressive diabetic nephropathy, was prominent in 22-month-old diabetic kidneys. The expression of tumor-necrosis factor-α in 22-month-old diabetic kidneys may play a role in inflammation, ER stress, and apoptosis. Thus, diabetes may accelerate the underlying kidney aging process present in old mice.
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U2 - 10.2353/ajpath.2010.090386
DO - 10.2353/ajpath.2010.090386
M3 - Article
C2 - 20363923
AN - SCOPUS:77952049573
SN - 0002-9440
VL - 176
SP - 2163
EP - 2176
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -