Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-13966
Wahl, P R; Le Hir, M; Vogetseder, A; Arcaro, A; Starke, A; Waeckerle-Men, Y; Serra, A L; Wuthrich, R P (2007). Mitotic activation of Akt signalling pathway in Han:SPRD rats with polycystic kidney disease. Nephrology, 12(4):357-363.
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AIM: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by an imbalance between tubular epithelial cell proliferation and apoptosis. We have previously shown that the mammalian target of rapamycin (mTOR) signalling pathway is aberrantly activated in the cystic kidneys of Han:SPRD rats with ADPKD. Because the Akt kinase is an upstream regulator of mTOR, we hypothesized that the activity of Akt could be enhanced in the kidneys of Han:SPRD rats. METHODS: Reverse transcription-polymerase chain reaction, western blot, enzyme-linked immunosorbent assay and immunohistochemistry were used to analyse Akt expression in rat polycystic kidneys. RESULTS: Wild-type (+/+) and heterozygous (Cy/+) Han:SPRD rats showed constitutive expression of Akt-1, -2 and -3 mRNA by reverse transcription-polymerase chain reaction analysis with no significant difference between Cy/+ and +/+ kidneys. Western blotting and enzyme-linked immunosorbent assay showed a significant increase in phosphorylated Akt in Cy/+ compared with +/+ kidneys. The pattern of immunoreactivity for phosphorylated Akt in kidney sections was the same in +/+ and in Cy/+ rats, with very low levels in interphase cells, but extremely bright signals in mitotic cells, beginning with the onset of the prophase. The in vivo incorporation of bromo-deoxyuridine revealed approximately a ninefold higher rate of proliferation in Cy/+ cyst epithelia compared with normal tubule epithelia in +/+ rats, while the expression of the cell cycle marker Ki67 revealed approximately a sixfold higher rate of proliferation. In summary, enhanced phosphorylation of Akt can be demonstrated in Cy/+ kidneys which correlates with a markedly elevated proliferation rate of epithelial cells in cysts. Mitotic but not resting cells display strong phosphorylation of Akt. CONCLUSION: Because Akt is a proximal target of mTOR, its inhibition with specific antagonists could be useful to prevent or halt cystogenesis in ADPKD.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology|
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||19 Mar 2009 15:52|
|Last Modified:||23 Nov 2012 17:39|
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