Accumulation of 8-hydroxy-2'-deoxyguanosine and mitochondrial DNA deletion in kidney of diabetic rats.
Oxidative stress may contribute to the pathogenesis of diabetic nephropathy. However, the detailed molecular mechanism remains uncertain. Here, we report oxidative mitochondrial DNA (mtDNA) damage and accumulation of mtDNA with a 4,834-bp deletion in kidney of streptozotocin-induced diabetic rats. At 8 weeks after the onset of diabetes, levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is a marker of oxidative DNA damage, were significantly increased in mtDNA from kidney of diabetic rats but not in nuclear DNA, suggesting the predominant damage of mtDNA. Semiquantitative analysis using PCR showed that the frequency of 4,834-bp deleted mtDNA was markedly increased in kidney of diabetic rats at 8 weeks, but it did not change at 4 weeks. Intervention by insulin treatment starting at 8 weeks rapidly normalized an increase in renal 8-OHdG levels of diabetic rats, but it did not reverse an increase in the frequency of deleted mtDNA. Our study demonstrated for the first time that oxidative mtDNA damage and subsequent mtDNA deletion may be accumulated in kidney of diabetic rats. This may be involved in the pathogenesis of diabetic nephropathy.
Kakimoto
Maiko
M
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Inoguchi
Toyoshi
T
Sonta
Toshiyo
T
Yu
Hai Yan
HY
Imamura
Minako
M
Etoh
Takashi
T
Hashimoto
Toshihiko
T
Nawata
Hajime
H
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000235:genetics*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000652:urine*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
D004272:DNA, Mitochondrial; D007004:Hypoglycemic Agents; D007328:Insulin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D011451:Prostaglandin-Endoperoxide Synthases; D003849:Deoxyguanosine