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Double inhibition of cAMP and mTOR signalling may potentiate the reduction of
cell growth in ADPKD cells
#MMPMID27278932
de Stephanis L
; Bonon A
; Varani K
; Lanza G
; Gafà R
; Pinton P
; Pema M
; Somlo S
; Boletta A
; Aguiari G
Clin Exp Nephrol
2017[Apr]; 21
(2
): 203-211
PMID27278932
show ga
BACKGROUND: ADPKD is a renal pathology caused by mutations of PKD1 and PKD2
genes, which encode for polycystin-1 (PC1) and polycystin-2 (PC2), respectively.
PC1 plays an important role regulating several signal transducers, including cAMP
and mTOR, which are involved in abnormal cell proliferation of ADPKD cells
leading to the development and expansion of kidney cysts that are a typical
hallmark of this disease. Therefore, the inhibition of both pathways could
potentiate the reduction of cell proliferation enhancing benefits for ADPKD
patients. METHODS: The inhibition of cAMP- and mTOR-related signalling was
performed by Cl-IB-MECA, an agonist of A3 receptors, and rapamycin, respectively.
Protein kinase activity was evaluated by immunoblot and cell growth was analyzed
by direct cell counting. RESULTS: The activation of A(3)AR by the specific
agonist Cl-IB-MECA causes a marked reduction of CREB, mTOR, and ERK
phosphorylation in kidney tissues of Pkd1 (flox/-): Ksp-Cre polycystic mice and
reduces cell growth in ADPKD cell lines, but not affects the kidney weight. The
combined sequential treatment with rapamycin and Cl-IB-MECA in ADPKD cells
potentiates the reduction of cell proliferation compared with the individual
compound by the inhibition of CREB, mTOR, and ERK kinase activity. Conversely,
the simultaneous application of these drugs counteracts their effect on cell
growth, because the inhibition of ERK kinase activity is lost. CONCLUSION: The
double treatment with rapamycin and Cl-IB-MECA may have synergistic effects on
the inhibition of cell proliferation in ADPKD cells suggesting that combined
therapies could improve renal function in ADPKD patients.
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