title: Global Toll-like receptor 4 knockout results in decreased renal inflammation, fibrosis and podocytopathy.
abstract: OBJECTIVE
  Type 1 diabetes mellitus (T1DM) is a pro-inflammatory state with increased toll-like receptor (TLR) activity. Inflammation is crucial in diabetic nephropathy (DN). We tested the effect of global deficiency of TLR4 on renal inflammation, fibrosis and podocytopathy using control (C) and streptozotocin (STZ) induced diabetic wildtype (WT) and TLR4-knockout (TLR4KO) mice.
  
  
  METHODS
  Following STZ treatment, mice were euthanized at 17weeks and plasma and kidneys collected.
  
  
  RESULTS
  Compared to C, STZ-WT mice had significantly increased macrophage and TLR4 immunostaining in kidney, significant increases in MyD88, Interferon Regulatory Factor-3, NFKappaB activity, TNF-Alpha, IL-6, and MCP-1; all these were significantly decreased in the STZ-TLR4KO compared to STZ-WT mice. Compared to C, there were significant increases in fibrosis markers (collagen 4, and transforming growth factor-beta) in STZ-WT which were significantly decreased in the STZ-TLR4KO versus STZ-WT. Podocyte numbers and podocin were decreased in the STZ-WT versus C and increased in the STZ-TLR4KO mice.
  
  
  CONCLUSIONS
  Global genetic deficiency of TLR4 also ameliorates renal inflammation, fibrosis and podocytopathy and could be important in DN.
authors.affiliation: Laboratory of Atherosclerosis and Metabolic Research, Sacramento, CA; Division of Endocrinology, Metabolism and Diabetes, Sacramento, CA; Department of Pathology and Internal Medicine, University of California Davis Medical Center, Sacramento, CA; VA Medical Center, Mather, CA. Electronic address: ijialal@ucdavis.edu.
authors.forename: Ishwarlal
authors.initials: I
authors.lastname: Jialal
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Major
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX. Electronic address: devaraj@bcm.edu.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Devaraj
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009393:Nephritis / Q000235:genetics* / Q000473:pathology; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D013311:Streptozocin; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D013311:Streptozocin
keywords: Diabetic nephropathy; Inflammation; Podocyte; Toll-like receptors