Journal Article

α‐MSH decreases apoptosis in ischaemic acute renal failure in rats: possible mechanism of this beneficial effect

Sang Kyung Jo, Su Young Yun, Kyung Hyun Chang, Dae Ryong Cha, Won Yong Cho, Hyoung Kyu Kim and Nam Hee Won

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 16, issue 8, pages 1583-1591
Published in print August 2001 | ISSN: 0931-0509
Published online August 2001 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/16.8.1583
α‐MSH decreases apoptosis in ischaemic acute renal failure in rats: possible mechanism of this beneficial effect

Show Summary Details

Preview

Background. Apoptosis frequently occurs in acute renal injury but the molecular mechanisms responsible for this distinct form of cell death are largely unknown. Fas belongs to the tumour necrosis factor (TNF)/nerve growth factor superfamily and engagement by Fas ligand induces apoptosis in various epithelial cells. To investigate the role of apoptosis and associated mechanisms, we examined the occurrence of apoptosis and Fas and Fas ligand expression, and the therapeutic effect of α‐melanocyte‐stimulating hormone (α‐MSH), a potent anti‐inflammatory cytokine in an ischaemic acute renal failure (ARF) rat model. We also examined neutrophil infiltration together with intercellular adhesion molecule‐1 (ICAM‐1) expression because of their possible involvement in apoptosis due to their ability to release various inflammatory cytokines and reactive oxygen species.

Methods. After unilateral nephrectomy in female Sprague–Dawley rats, the renal artery of the contralateral kidney was clamped for 40 min and reperfused. α‐MSH or vehicle was injected intraperitoneally immediately after reperfusion and at 1, 6, or 24 h after reperfusion. The expression of Fas and Fas ligand was studied by western blot analysis and semiquantitative reverse transcription polymerase chain reaction (RT‐PCR). Apoptosis was assessed by the terminal deoxynucleotidyl transferase‐mediated dUTP–biotin nick‐end labelling (TUNEL) method, and neutrophil infiltration by naphthol AS‐D chloracetate staining. The degree of apoptosis, neutrophil infiltration, and Fas and Fas ligand, and ICAM‐1 expression, as well as biochemical and histological data were compared between the α‐MSH and the vehicle‐treated groups.

Results. Intraperitoneally administered α‐MSH significantly reduced renal injury, measured by blood urea nitrogen (BUN) and creatinine and by the degree of tubular necrosis (109.6±7.1/54.7±3.1 mg/dl for BUN, and 1.6±0.2/1.03±0.06 mg/dl for creatinine 24 h after ischaemia) (5.4±0.8/2.6±0.3 for injury score 24 h after ischaemia). Ischaemia caused an increase in Fas and Fas ligand expression and was accompanied by morphological evidence of apoptosis. α‐MSH significantly reduced the degree of apoptosis, as well as Fas and Fas ligand expression (mean apoptotic cell number, 41.7±3.5/14.2±2.2 per ×200 field at 24 h after ischaemia. Fas protein expression: sham, 1409±159 DI (densitometric index); vehicle/α‐MSH, 2818±635/1306±321 DI at 24 h and 5542±799/2867±455 DI at 72 h after ischaemia. Fas ligand protein expression: sham, 1221±181 DI; vehicle/α‐MSH, 2590±85/1279±169 DI at 4 h, 4376±268/2432±369 DI at 24 h and 5200±648/2253.7±1104 DI at 72 h after ischaemia). Neutrophil infiltration and ICAM‐1 expression were also significantly reduced in α‐MSH group (neutrophil infiltration: vehicle/ α‐MSH, 5.05±1.8/1.59±0.4) (ICAM‐1 expression, vehicle/α‐MSH 0.46±0.21/0.29±0.19).

Conclusion. These results suggest that apoptosis clearly contributes to tubular cell loss in ischaemia/reperfusion (I/R) injury possibly by neutrophil‐mediated pathways or an increase in Fas–Fas ligand expression. The observed beneficial effect of α‐MSH could be related to these mechanisms.

Keywords: acute renal failure; apoptosis; ICAM‐1; α‐MSH; Fas; neutrophil

Journal Article.  5086 words.  Illustrated.

Subjects: Nephrology

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.