期刊
DIABETOLOGIA
卷 57, 期 2, 页码 424-434出版社
SPRINGER
DOI: 10.1007/s00125-013-3115-6
关键词
Adeno-associated virus; db/db mice; Diabetic nephropathy; Gene therapy; NLRP3 inflammasome; NRF2; Thrombomodulin domain 1
资金
- Department of Health, Executive Yuan [DOH97-TD-I-11-TM006]
- Ministry of Economic Affairs [100-EC-17-A-19-S1-161]
- National Science Council of Taiwan, Republic of China [NSC 101-2321-B-016-003]
Chronic inflammatory processes have been increasingly shown to be involved in the pathogenesis of diabetes and diabetic nephropathy. Recently, we demonstrated that a lectin-like domain of thrombomodulin (THBD), which is known as THBD domain 1 (THBDD1) and which acts independently of protein C activation, neutralised an inflammatory response in a mouse model of sepsis. Here, therapeutic effects of gene therapy with adeno-associated virus (AAV)-carried THBDD1 (AAV-THBDD1) were tested in a mouse model of type 2 diabetic nephropathy. To assess the therapeutic potential of THBDD1 and the mechanisms involved, we delivered AAV-THBDD1 (10(11) genome copies) into db/db mice and tested the effects of recombinant THBDD1 on conditionally immortalised podocytes. A single dose of AAV-THBDD1 improved albuminuria, renal interstitial inflammation and glomerular sclerosis, as well as renal function in db/db mice. These effects were closely associated with: (1) inhibited activation of the nuclear factor kappa B (NF-kappa B) pathway and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome; (2) promotion of nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear translocation; and (3) suppression of mitochondria-derived apoptosis in the kidney of treated mice. AAV-THBDD1 gene therapy resulted in improvements in a model of diabetic nephropathy by suppressing the NF-kappa B-NLRP3 inflammasome-mediated inflammatory process, enhancing the NRF2 antioxidant pathway and inhibiting apoptosis in the kidney.
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