Podocyte injury induced by albumin overload in vivo and in vitro: involvement of TGF-beta and p38 MAPK.
BACKGROUND
Proteinuria is a well-established exacerbating factor in chronic kidney disease. Although the mechanisms of albumin-induced tubulointerstitial damage have been extensively studied, the influence of proteinuria on podocytes has not been sufficiently elucidated. The present study examined the effect of albumin overload on podocytes in vivo and in vitro and explored the underlying mechanisms.


METHODS
Rat podocytes were exposed to albumin overload in vivo by the intraperitoneal injection of albumin over 2 days whilst cultured podocytes were subjected to albumin in vitro. We analyzed albumin uptake, podocyte apoptosis, staining for F-actin and nephrin and involvement of TGF-beta1 and p38 MAPK cascades.


RESULTS
Rats administered albumin exhibited massive proteinuria and podocyte injury manifested by decreased nephrin immunostaining and foot process effacement. These abnormalities were accompanied by albumin deposition, TGF-beta1 upregulation, p38 MAPK phosphorylation and an increased number of glomerular TUNEL-positive cells. Exposure of cultured podocytes to albumin caused actin disarrangement and apoptosis. Podocyte injury was preceded by albumin uptake, induction of TGF-beta1 and phosphorylated p38 MAPK. Treatment of podocytes with anti-TGF-beta1 neutralizing antibody or SB203580 significantly reduced the albumin-induced injury.


CONCLUSIONS
These results indicate that albumin overload in vivo and in vitro promotes podocyte injury mainly via TGF-beta1/p38 MAPK pathways.
Yoshida
Shigetaka
S
Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Nagase
Miki
M
Shibata
Shigeru
S
Fujita
Toshiro
T
D000818:Animals; D002478:Cells, Cultured; D008297:Male; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D011507:Proteinuria / Q000139:chemically induced* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000633:toxicity*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D012709:Serum Albumin; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases