Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease

Abstract

In autosomal dominant polycystic kidney disease (ADPKD), abnormal proliferation of tubular cells drives cyst development and growth. Sirolimus, an inhibitor of the protein kinase mammalian target of rapamycin (mTOR) and a potent anti-proliferative agent, decreases cyst growth in several genetically distinct rodent models of polycystic kidney disease (PKD). We determined here the effect of sirolimus on renal cyst growth in Pkd2WS25/- mice; an ortholog of human ADPKD involving mutation of the Pkd2 gene. In Pkd2WS25/- mice treated with sirolimus, both the two kidney/total body weight (2K/TBW) ratio and the cyst volume density (CVD) were significantly decreased by over half compared with untreated mice suffering with PKD. However, there was no effect on the increased blood urea nitrogen (BUN) levels as an index of kidney function. There are two distinct complexes containing mTOR depending on its binding partners: mTORC1 and mTORC2. Western blot analysis of whole kidney lysates and immunohistochemistry of the cysts found that phospho-S6 ribosomal protein, a marker of mTORC1 activity, was increased in Pkd2WS25/- mice and its phosphorylation was decreased by sirolimus treatment. Phospho-Akt at serine 473, a marker associated with mTORC2 activity, was not different between Pkd2WS25/- mice and normal littermate controls. Hence, our study found that inhibition of mTORC1 by sirolimus correlated with decreased renal cyst growth in this model of human ADPKD but had no effect on the decline in renal function.

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

“…Previous studies also showed beneficial effects of rapamycin in two orthologous PKD mouse models. 30,31 High-dose sirolimus (blood level of 22 ng/ml) has been shown to reduce cyst growth in Pkd2 WS25/-mice without improvement of renal function, 31 whereas rapamycin reduced cyst growth and improved renal function in a conditional Pkd1-knockout model. In this model, drug levels in circulation were not measured.…”

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

“…93 First shown in the Cy/+ rat model, 94 the efficacy of mTORC1 inhibitors to reduce cyst growth and to ameliorate disease progression was subsequently demonstrated in several animal models of cystic kidney disease, including Pkd1-deficient mice. 90,[95][96][97][98][99][100] Despite these encouraging preclinical data, mTOR inhibitors did not yield the expected benefits in patients with ADPKD. While everolimus slowed cyst growth in ADPKD patients, this inhibition did not translate into an improvement of renal function.…”

Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease

“…Furthermore, treatment of PKD rodent models with mTOR inhibitors, such as rapamycin, greatly improves the cystic phenotype. [5][6][7][8][9][10][11] Because mTOR inhibitors have already been in clinical use as immunosuppressant drugs, these studies rapidly led to several clinical trials to determine whether they are effective in patients with APDKD. [12][13][14] Unfortunately, although not yet fully conclusive, the results of these trials have been largely disappointing.…”

“…2 Currently, no treatment for ADPKD is available, and most patients eventually require lifelong dialysis or kidney transplantation. We 3,4 and others [5][6][7][8][9][10][11] have demonstrated that the mammalian target of rapamycin (mTOR) pathway is hyperactivated in PKD rodent models and human ADPKD. Furthermore, treatment of PKD rodent models with mTOR inhibitors, such as rapamycin, greatly improves the cystic phenotype.…”