A possible role of thioredoxin interacting protein in the pathogenesis of streptozotocin-induced diabetic nephropathy.
Oxidative stress has been suggested to play an important role in the pathogenesis of diabetic nephropathy because it increases under diabetic conditions and is known to induce cellular dysfunction in a wide variety of cells. To protect cells against oxidative stress, cells possess defensive mechanisms such as intracellular antioxidants. Although it has been reported that central enzymes in the antioxidative defense mechanisms of the cell are induced under hyperglycemic conditions, the oxidative stress level remains high. On the other hand, there are endogenous inhibitors of antioxidants, such as thioredoxin interacting protein (Txnip). In the present study, the relationship between diabetic nephropathy and Txnip was investigated using streptozotocin (STZ)-induced diabetic mice. Eight-week-old male C57BL/6 mice were treated with either STZ or citrate vehicle. After 24 weeks of treatment, diabetic nephropathy and oxidative stress were assessed by biochemical analyses of urine and histological analyses of the kidneys. In addition, the expression of Type IV collagen alpha1 chain (Col4A1), Transforming growth factor-beta (TGF-beta), and Txnip were evaluated by real-time polymerase chain reaction. Albuminuria, renal hypertrophy, and expansion of the mesangial area, which are the hallmarks of diabetic nephropathy, were confirmed in the diabetic mice. The mRNA expression of COL4A1 and TGF-beta was dramatically increased in diabetic mice in comparison with the control mice. Moreover, associated with the increased renal expression of Txnip, diabetic conditions increased oxidative stress as determined by urinary excretion of 8-hydroxy-2'-deoxyguanosine and acrolein adduct, which are oxidative stress markers. Moreover, Txnip may be a therapeutic target in diabetic nephropathy.
Hamada
Yasuhiro
Y
Division of Nephrology and Dialysis Center, Kobe University Graduate School of Medicine, Kobe, Japan.
Fukagawa
Masafumi
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000171:Acrolein / Q000652:urine; D000419:Albuminuria; D000818:Animals; D015415:Biomarkers; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D024141:Collagen Type IV / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006984:Hypertrophy; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D013311:Streptozocin / Q000633:toxicity; D013879:Thioredoxins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D002352:Carrier Proteins; D024141:Collagen Type IV; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C445672:Txnip protein, mouse; D013879:Thioredoxins; D013311:Streptozocin; D000171:Acrolein; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine