Diabetologia (2014) 57:214–223
DOI 10.1007/s00125-013-3064-0
Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)- aploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity
Ji Hee Lim & Dong-Ye Youn & Hyung Jae Yoo & Hye Hyeon Yoon & Min Young Kim & Sungjin Chung & Yong-Soo Kim & Yoon Sik Chang & Cheol Whee Park & Jeong-Hwa Lee
J. H. Lim: M. Y. Kim: S. Chung : Y.<S. Kim: Y. S. Chang :
C. W. Park (*)
Department of Internal Medicine, College of Medicine,
The Catholic University of Korea, 222 Banpo-daero, Seocho-gu,
Seoul 137-701, South Korea
e-mail: cheolwhee@hanmail.net
D.<Y. Youn : H. J. Yoo : H. H. Yoon : J.<H. Lee (*)
Department of Biochemistry, College of Medicine,
The Catholic University of Korea, 222 Banpo-daero, Seocho-gu,
Seoul 137-701, South Korea
e-mail: leejh@catholic.ac.kr
H. J. Yoo : H. H. Yoon : J.<H. Lee
Cancer Evolution Research Center, College of Medicine,
The Catholic University of Korea, Seoul, South Korea
Abstract
Aims/hypothesis B cell CLL/lymphoma 2 (BCL-2)-interacting cell death suppressor (BIS), known as an anti-stress and antiapoptotic
protein, has been reported to modulate susceptibility to oxidative stress. This study investigated the potential role of
BIS as an antioxidant protein in diabetic nephropathy.
Methods Diabetes was induced in BIS-heterozygote (BIS-HT) mice via streptozotocin injections and the resulting phenotypes
were compared with those of BIS-wild-type (BIS-WT) mice over the 20 weeks following diabetes induction.
Results Renal injuries, represented by increased plasma creatinine levels and increased albuminuria, were greater in diabetic
BIS-HT mice than in diabetic BIS-WT mice, and were accompanied by a significant increase in reactive oxygen
species (ROS) and oxidative stress markers. Moreover, renalpathological changes and the apoptotic process were accelerated
in diabetic BIS-HT mice compared with diabetic BIS-WT mice with the same degree of hyperglycaemia; all
were restored by 4-hydroxy-2,2,6,6-tetramethylpiperidine-Noxyl (tempol) treatment. The levels of NADPH oxidase and
related proteins were not significantly higher in diabetic BIS-HT mice compared with diabetic BIS-WT mice. However,
levels of superoxide dismutase (SOD)1 and SOD2 increased on the induction of diabetes in BIS-WT mice but not in BIS-HT
mice, correlating with the total SOD activity. An in vitro study showed that knockdown of BIS production also resulted in
impaired induction of SOD activity as well as SOD levels in HK-2 and NMS cells, concomitant with significant ROS
accumulation.
Conclusion/interpretation Our results suggest that the decreased antioxidant capacity of BIS aggravates diabetic nephropathy
in diabetic BIS-HT mice, possibly as a result of the disruption in the regulation of SOD protein quality under oxidative stress.