The effect of alpha-melanocyte-stimulating hormone on renal tubular cell apoptosis and tubulointerstitial fibrosis in cyclosporine A nephrotoxicity.
BACKGROUND
The pathogenesis of cyclosporine A (CsA)-induced nephrotoxicity has been known to be secondary to hemodynamic changes, but increasing evidence indicates that CsA has a direct toxicity to renal tubular cells, leading to their apoptosis and tubulointerstitial fibrosis. This study evaluated the mechanism for CsA-induced tubular cell apoptosis, tubulointerstitial fibrosis and its associated proteins, and the therapeutic effects of alpha-melanocyte-stimulating hormone (MSH) on them.


METHODS
Male Sprague-Dawley rats fed with a low-sodium diet were divided into three treatment groups: group A (vehicle-injected group), group B (CsA 15 mg/kg-injected group), and group C(CsA+alpha-MSH-injected group). After 42 days, creatinine clearance; blood CsA level; apoptosis; inflammation and tubulointerstitial fibrosis in renal tissue; and the expression of Bax, Bcl2, Fas, FasL, and transforming growth factor (TGF)-beta protein were determined.


RESULTS
CsA-induced tubular cell apoptosis; cellular infiltration; and increase of Fas, Bax, TGF-beta protein expression with significant tubulointerstitial fibrosis, and reduced Bcl2 protein expression. alpha-MSH treatment prevented the Bax and TGF-beta protein increase and induced Bcl2 protein increase, together with reduction of apoptosis, inflammation, and tubulointerstitial fibrosis.


CONCLUSIONS
These findings suggest that chronic CsA nephrotoxicity is related to Bax and Bcl2-related apoptosis pathways, and that alpha-MSH can attenuate the CsA-induced tubulointerstitial fibrosis as well as tubular cell apoptosis.
Lee
So Young
SY
Department of Internal Medicine, Eulji College of Medicine, Seoul, Korea.
Jo
Sang Kyung
SK
Cho
Won Yong
WY
Kim
Hyoung Kyu
HK
Won
Nam Hee
NH
D000818:Animals; D000954:Antigens, Surface; D017209:Apoptosis / Q000187:drug effects*; D002908:Chronic Disease; D016572:Cyclosporine / Q000506:poisoning*; D005355:Fibrosis; D007166:Immunosuppressive Agents / Q000506:poisoning*; D020287:In Situ Nick-End Labeling; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000521:alpha-MSH / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D000954:Antigens, Surface; C494828:Bax protein, rat; D007166:Immunosuppressive Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D000521:alpha-MSH; D016572:Cyclosporine