Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity.
OBJECTIVE
B cell CLL/lymphoma 2 (BCL-2)-interacting cell death suppressor (BIS), known as an anti-stress and anti-apoptotic 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, renal pathological 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-N-oxyl (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.


CONCLUSIONS
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.
Ji Hee
JH
Lim
Dong-Ye
DY
Youn
Hyung Jae
HJ
Yoo
Hye Hyeon
HH
Yoon
Min Young
MY
Kim
Sungjin
S
Chung
Yong-Soo
YS
Kim
Yoon Sik
YS
Chang
Cheol Whee
CW
Park
Jeong-Hwa
JH
Lee
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1