Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis

Shun Min Yang, Shuk Man Ka, Hua Lin Wu, Yu Chuan Yeh, Cheng Hsiang Kuo, Kuo Feng Hua, Guey Yueh Shi, Yi Jen Hung, Fone Ching Hsiao, Sung Sen Yang, Yi Shing Shieh, Shih Hua Lin, Chyou Wei Wei, Jeng Shin Lee, Chu Yi Yang, Ann Chen

研究成果: Article同行評審

69 引文 斯高帕斯(Scopus)

摘要

Aims/hypothesis: 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. Methods: To assess the therapeutic potential of THBDD1 and the mechanisms involved, we delivered AAV-THBDD1 (1011 genome copies) into db/db mice and tested the effects of recombinant THBDD1 on conditionally immortalised podocytes. Results: 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 κB (NF-κB) 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. Conclusions/interpretation: AAV-THBDD1 gene therapy resulted in improvements in a model of diabetic nephropathy by suppressing the NF-κB-NLRP3 inflammasome-mediated inflammatory process, enhancing the NRF2 antioxidant pathway and inhibiting apoptosis in the kidney.

原文English
頁(從 - 到)424-434
頁數11
期刊Diabetologia
57
發行號2
DOIs
出版狀態Published - 2014 二月

All Science Journal Classification (ASJC) codes

  • 內科學
  • 內分泌學、糖尿病和代謝

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