Journal Article

Adrenomedullin protects against oxidative stress-induced podocyte injury as an endogenous antioxidant

Shigeyoshi Oba, Masayo Hino and Toshiro Fujita

in Nephrology Dialysis Transplantation

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

Volume 23, issue 2, pages 510-517
Published in print February 2008 | ISSN: 0931-0509
Published online November 2007 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfm600
Adrenomedullin protects against oxidative stress-induced podocyte injury as an endogenous antioxidant

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Background. We previously reported that puromycin aminonucleoside (PAN) increased adrenomedullin (AM) secretion and AM mRNA expression in podocytes, through overproduction of oxidative stress. To clarify the cytoprotective role of AM as antioxidative and antiapoptotic substance in podocytes, we investigated the effect of exogenous AM and AM antagonist on PAN-induced apoptosis in conditionally immortalized murine podocytes.

Methods. The expression of AM, RAMP 2 and RAMP 3 was investigated using real-time PCR, western blotting analysis and immunofluorescence microscopy. Reactive oxygen species (ROS) production was measured by CM-H2DCFDA fluorescence intensity method. The percentage of apoptotic cells was measured by Hoechst 33342 staining.

Results. PAN (100 μg/ml) significantly (P < 0.01) increased ROS production, associated with an increase in apoptosis; the percentage of apoptotic cells is 5.3% + 0.05% (P < 0.01) with 36 h treatment of PAN compared to 0.24 + 0.16% with no treatment. Several antioxidants could markedly reduce PAN-induced apoptosis in cultured podocytes, suggesting that PAN-induced apoptosis might be attributable to the overproduction of ROS. Accordingly, the administration of exogenous AM (10−6 M) could significantly reduce not only ROS production via a PKA-dependent pathway, but also the resultant apoptosis induced by PAN. AM antagonists, CGRP8-37, augmented PAN-induced apoptosis, associated with increased ROS production, 2.2- and 2.3-Fold, respectively. RAMP 2 and RAMP 3 could be detected in podocytes and glomeruli.

Conclusions. This suggests that ROS-induced up-regulation of AM with PAN could counteract ROS-induced apoptosis, by the suppression of ROS production. Therefore, AM might have the endogenous antioxidant potential to protect against ROS-induced podocyte injury.

Keywords: adrenomedullin; aminonucleoside; antioxidants; apoptosis; oxidative stress; podocyte; proteinuria; puromycin; reactive oxygen species

Journal Article.  5010 words.  Illustrated.

Subjects: Nephrology

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