title: Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy.
abstract: OBJECTIVE
  Inflammation and fibrosis are pathological mechanisms that are partially regulated by cell signalling through the p38 mitogen-activated protein kinase (MAPK) pathway. Elements of the diabetic milieu such as high glucose and advanced glycation end-products induce activation of this pathway in renal cells. Therefore, we examined whether p38 MAPK signalling is associated with the development of human and experimental diabetic nephropathy.
  
  
  METHODS
  Immunostaining identified phosphorylated (active) p38 MAPK in human biopsies with no abnormality ( n=6) and with Type 2 diabetic nephropathy ( n=12). Changes in kidney levels of phosphorylated p38 were assessed by immunostaining and western blotting in mice with streptozotocin-induced Type 1 diabetes that had been killed after 0.5, 2, 3, 4 and 8 months, and in Type 2 diabetic db/db mice at 2, 4, 6 and 8 months of age.
  
  
  RESULTS
  Phosphorylated p38 was detected in some intrinsic cells in normal human kidney, including podocytes, cortical tubules and occasional interstitial cells. Greater numbers of these phosphorylated p38+ cells were observed in diabetic patients, and phosphorylated p38 was identified in accumulating interstitial macrophages and myofibroblasts. A similar pattern of p38 activation was observed in both mouse models of diabetes. In mice, kidney levels of phosphorylated p38 increased (2-6 fold) following the onset of Type 1 and Type 2 diabetes. In both mouse models, interstitial phosphorylated p38+ cells were associated with hyperglycaemia, increased HbA(1)c levels and albuminuria. Further assessment of streptozotocin-induced diabetic nephropathy showed that interstitial phosphorylated p38+ cells correlated with interstitial fibrosis (myofibroblasts, collagen).
  
  
  CONCLUSIONS
  Increased p38 MAPK signalling is a feature of human and experimental diabetic nephropathy. Time course studies in mouse models suggest that phosphorylation of p38 plays a pathological role, particularly in the development of interstitial fibrosis.
authors.affiliation: Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Adhikary
authors.affiliation: Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Chow
authors.affiliation: Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: D J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.affiliation: Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Stambe
authors.affiliation: Department of Anatomical Pathology, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Dowling
authors.affiliation: Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: R C
authors.initials: RC
authors.lastname: Atkins
authors.affiliation: Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. gtesch@hotmail.com.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia. gtesch@hotmail.com.
authors.forename: G H
authors.initials: GH
authors.lastname: Tesch
mesh_terms: D000818:Animals; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D003404:Creatinine; D006442:Glycated Hemoglobin; D048051:p38 Mitogen-Activated Protein Kinases