Deficiency of polycystic kidney disease-1 gene (PKD1) expression increases A3 adenosine receptors in human renal cells

Pharmacological, molecular and biochemical findings show that a siRNA-dependent PC1-depletion in HEK293 cells and a PKD1-nonsense mutation in cyst-derived cell lines result in increased expression of the A3 adenosine receptor via an NFkB-dependent mechanism. Interestingly, A3 adenosine receptor levels result higher in ADPKD than in normal renal tissues. Furthermore, the stimulation of this receptor subtype with the selective agonist Cl-IB-MECA causes a reduction in both cytosolic cAMP and cell proliferation in both PC1-deficient HEK293 cells and cystic cells. The observation that the increase in A3 adenosine receptor density is consistent with that in A3 protein and mRNA levels strongly indicates that loss of PKD1 gene expression leads to increased expression of the A3 gene. PC1 depletion may cause an increase in A3 gene expression via cAMP production in cystic cells which might upregulate the A3 promoter activity. Our results suggest that NFkB, which is markedly activated in PC1-deficient and cystic cells, plays an important role in modulating A3 adenosine receptors expression in cystic cells. In conclusion, these data shows that cystic cells “in vitro” and ADPKD kidneys express increased A3 adenosine receptor levels, and upon its activation, the modulation of cAMP and of key signalling proteins leads to inhibition of the growth of cystic cells suggesting that A3 agonists could be potentially useful in the treatment of ADPKD.