Autosomal dominant polycystic kidney disease (
ADPKD) is the most common life-threatening
hereditary disease in the USA. In human
ADPKD studies,
sirolimus, a
mammalian target of rapamycin complex 1 (
mTORC1) inhibitor, had little
therapeutic effect. While
sirolimus robustly inhibits
mTORC1, it has a minimal effect on mTOR complex 2 (
mTORC2).
Polycystic kidneys of Pkd2WS25/- mice, an orthologous model of human
ADPKD caused by a mutation in the Pkd2 gene, had an early increase in pS6 (marker of
mTORC1) and pAktSer(473) (marker of
mTORC2). To investigate the effect of combined
mTORC1 and 2 inhibition, Pkd2WS25/- mice were treated with an mTOR
anti-sense oligonucleotide (ASO) that blocks mTOR expression thus inhibiting both
mTORC1 and 2. The mTOR ASO resulted in a significant decrease in
mTOR protein, pS6 and pAktSer(473). Pkd2WS25/- mice treated with the ASO had a normalization of kidney weights and kidney function and a marked decrease in
cyst volume. The mTOR ASO resulted in a significant decrease in proliferation and apoptosis of tubular epithelial cells. To demonstrate the role of
mTORC2 on
cyst growth, Rictor, the functional component of
mTORC2, was silenced in Madin-Darby canine kidney cell
cysts grown in 3D cultures. Silencing Rictor significantly decreased
cyst volume and expression of pAktSer(473). The decreased
cyst size in the Rictor silenced cells was reversed by introduction of a constitutively active Akt1. In vitro, combined
mTORC1 and 2 inhibition reduced
cyst growth more than inhibition of
mTORC1 or 2 alone. In conclusion, combined
mTORC1 and 2 inhibition has therapeutic potential in
ADPKD.