Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy.
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.
Sakai
Norihiko
N
Department of Gastroenterology and Nephrology, Division of Blood Purification, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Wada
Takashi
T
Furuichi
Kengo
K
Iwata
Yasunori
Y
Yoshimoto
Keiichi
K
Kitagawa
Kiyoki
K
Kokubo
Satoshi
S
Kobayashi
Motoo
M
Hara
Akinori
A
Yamahana
Junya
J
Okumura
Toshiya
T
Takasawa
Kazuya
K
Takeda
Shin-Ichi
S
Yoshimura
Mitsuhiro
M
Kida
Hiroshi
H
Yokoyama
Hitoshi
H
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
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