title: Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy.
abstract: BACKGROUND
  The involvement of mitogen-activated protein kinase (MAPK) in human diabetic nephropathy has not been fully investigated.
  
  
  METHODS
  The presence of cells positive for the phosphorylated MAPK family (phosphorylated extracellular signal-regulated kinase [p-ERK], phosphorylated p38MAPK [p-p38MAPK]) was investigated immunohistochemically in kidneys of 30 patients with diabetic nephropathy. In addition, 10 patients with minimal change nephrotic syndrome, 10 patients with thin basement membrane disease, and 5 patients with benign nephrosclerosis were studied as disease controls. The presence of activated nuclear factor-kappaB (p65)-positive cells also was evaluated in kidney specimens.
  
  
  RESULTS
  In patients with diabetic nephropathy, p-ERK, p-p38MAPK, and p65 were observed in mesangial cells, endothelial cells, podocytes, tubular epithelial cells, and mononuclear infiltrates in interstitium. Numbers of p-ERK-, p-p38MAPK-, and p65-positive cells in both glomeruli and interstitium in patients with diabetic nephropathy were higher than those in controls. In particular, the number of glomerular p-ERK-positive cells in patients with diabetic nephropathy increased in accordance with the progression of glomerular lesions and correlated well with the number of glomerular p65-positive cells (r = 0.654; P < 0.01; n = 30). Conversely, the number of p-p38MAPK-positive cells in glomeruli did not correlate with glomerular lesions. However, the number of tubulointerstitial p-p38MAPK-positive cells in patients with diabetic nephropathy reflected the severity of tubulointerstitial lesions, and numbers of those in the interstitium increased with good correlation to numbers of tubulointerstitial p65-positive cells (r = 0.757; P < 0.01; n = 30) and interstitial CD68-positive macrophages (r = 0.647; P < 0.05; n = 30) and urinary monocyte chemoattractant protein-1 levels (r = 0.605; P < 0.05; n = 30).
  
  
  CONCLUSIONS
  These results suggest that MAPK phosphorylation contributes to human diabetic nephropathy. In particular, ERK and p38MAPK may be distinctly involved in glomerular and tubulointerstitial lesions in human diabetic nephropathy.
authors.affiliation: Department of Gastroenterology and Nephrology, Division of Blood Purification, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Sakai
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Kengo
authors.initials: K
authors.lastname: Furuichi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Iwata
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Kiyoki
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kokubo
authors.forename: Motoo
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Akinori
authors.initials: A
authors.lastname: Hara
authors.forename: Junya
authors.initials: J
authors.lastname: Yamahana
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okumura
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takasawa
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokoyama
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D048049:Extracellular Signal-Regulated MAP Kinases; D016328:NF-kappa B; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases; C067980:CD68 antigen, human; D000097382:CD68 Molecule