Novalic, Zlata and van der Wal, Annemieke M. and Leonhard, Wouter N. and Koehl, Gudrun and Breuning, Martijn H. and Geissler, Edward K. and de Heer, Emile and Peters, Dorien J. M. (2012) Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 23 (5). pp. 842-853. ISSN 1046-6673,
Full text not available from this repository. (Request a copy)Abstract
Inhibition of the mammalian target of rapamycin (mTOR) shows beneficial effects in animal models of polycystic kidney disease (PKD); however, two clinical trials in patients with autosomal dominant PKD failed to demonstrate a short-term benefit in either the early or progressive stages of disease. The stage of disease during treatment and the dose of mTOR inhibitors may account for these differing results. Here, we studied the effects of a conventional low dose and a higher dose of sirolimus (blood levels of 3 ng/ml and 30-60 ng/ml, respectively) on mTOR activity and renal cystic disease in two Pkd1-mutant mouse models at different stages of the disease. When initiated at early but not late stages of disease, high-dose treatment strongly reduced mTOR signaling in renal tissues, inhibited cystogenesis, accelerated cyst regression, and abrogated fibrosis and the infiltration of immune cells. In contrast, low-dose treatment did not significantly reduce renal cystic disease. Levels of p-S6Rp(Ser240/244), which marks mTOR activity, varied between kidneys; severity of the renal cystic phenotype correlated with the level of mTOR activity. Taken together, these data suggest that long-term treatment with conventional doses of sirolimus is insufficient to inhibit mTOR activity in renal cystic tissue. Mechanisms to increase bioavailability or to target mTOR inhibitors more specifically to kidneys, alone or in combination with other compounds, may improve the potential for these therapies in PKD.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EPITHELIAL-CELLS; RAT MODEL; 1 GENE; PKD1; RAPAMYCIN; PROGRESSION; PATHWAY; GROWTH; INACTIVATION; CYSTOGENESIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 May 2020 06:03 |
| Last Modified: | 15 May 2020 06:03 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18821 |
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