title: 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.
abstract: OBJECTIVE
  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 (10(11) 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
  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.
authors: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gung Road, Taipei, Taiwan, Republic of China.
authors: Shun-Min
authors: SM
authors: Yang
authors: Shuk-Man
authors: SM
authors: Ka
authors: Hua-Lin
authors: HL
authors: Wu
authors: Yu-Chuan
authors: YC
authors: Yeh
authors: Cheng-Hsiang
authors: CH
authors: Kuo
authors: Kuo-Feng
authors: KF
authors: Hua
authors: Guey-Yueh
authors: GY
authors: Shi
authors: Yi-Jen
authors: YJ
authors: Hung
authors: Fone-Ching
authors: FC
authors: Hsiao
authors: Sung-Sen
authors: SS
authors: Yang
authors: Yi-Shing
authors: YS
authors: Shieh
authors: Shih-Hua
authors: SH
authors: Lin
authors: Chyou-Wei
authors: CW
authors: Wei
authors: Jeng-Shin
authors: JS
authors: Lee
authors: Chu-Yi
authors: CY
authors: Yang
authors: Ann
authors: A
authors: Chen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018180:Thrombomodulin / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C569169:THBD protein, mouse; D018180:Thrombomodulin