title: Human cortical fibroblast responses to high glucose and hypoxia.
abstract: OBJECTIVE
  Approximately 30% of individuals with diabetes mellitus are susceptible to diabetic nephropathy, whereas ischemic injury uniformly induces renal impairment. As matrix accumulation correlates with progressive renal disease we assessed parameters associated with matrix turnover in response to high glucose +/- hypoxia in human cortical fibroblasts (CF).
  
  
  METHODS
  CF were grown to confluence and exposed to media containing 5 or 25 mmol/l D-glucose for 72 h with or without a superimposed hypoxic insult.
  
  
  RESULTS
  High glucose increased cellular protein content (p < 0.05). Combined high glucose and hypoxia induced a further increase in cellular protein content (p < 0.005), suggestive of a synergistic hypertrophic effect. MMP secretion corresponded inversely with changes in TIMP expression. In cell cultures derived from 2/3 of patients, high glucose increased MMP-9 (p < 0.0005) and MMP-2 (p < 0.005) while TIMP-1 was reduced (p = 0.05). In the remaining cell cultures derived from 1/3 of patients, MMP-2 was reduced (p < 0.0001) while TIMP-1 and TIMP-2 were both increased (p < 0.05). In contrast, hypoxia induced uniform reductions in MMP-9 and MMP-2 in both normal and high glucose conditions. High glucose increased the expression of PAI-1 mRNA (p < 0.05) in all patients independent of changes in the MMP-TIMP axis.
  
  
  CONCLUSIONS
  In summary, variability was observed in the MMP-TIMP axis following exposure to high glucose. In contrast, high glucose uniformly induces PAI-1 expression. Hypoxic insults uniformly reduce matrix breakdown independent of the prevailing glucose conditions.
authors.affiliation: Department of Medicine, University of Sydney, Kolling Institute, Royal North Shore Hospital, St. Leonards, NSW, Australia.
authors.forename: Weier
authors.initials: W
authors.lastname: Qi
authors.forename: Philip
authors.initials: P
authors.lastname: Poronnik
authors.forename: Barbara
authors.initials: B
authors.lastname: Young
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Jackson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Field
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
mesh_terms: D002452:Cell Count; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007672:Kidney Cortex / Q000166:cytology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D011506:Proteins; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases; D005947:Glucose