Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease.

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.

• Authors: Zlata Novalic, Annemieke M van der Wal, Wouter N Leonhard, Gudrun Koehl, Martijn H Breuning, Edward K Geissler, Emile de Heer, Dorien J M Peters
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 23 Issue 5 Pg. 842-53 (May 2012) ISSN: 1533-3450 [Electronic] United States
• PMID: 22343118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• mTOR protein, mouse
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Dose-Response Relationship, Drug
• Female
• Immunosuppressive Agents (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Polycystic Kidney Diseases (drug therapy, pathology)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, physiology)