Published in:
01-02-2014 | Article
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
Published in: Diabetologia | Issue 2/2014
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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.