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

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)424-434
Number of pages11
JournalDiabetologia
Volume57
Issue number2
DOIs
Publication statusPublished - 2014 Feb

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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