Up-regulation of the gene encoding protein kinase A type Iα regulatory subunit in nodular hyperplasia of parathyroid glands in patients with chronic renal failure

Context: Hyperplasia of parathyroid glands in patients with chronic renal failure is classified into diffuse (DH) and nodular (NH) types, and NH is often refractory to routine medical therapy. Objective: Although it is considered that the parenchymal cells initially proliferate diffusely and then some of them are transformed to form nodules consisting of monoclonal cells, the underlying molecular mechanism for such a transformation is not fully understood. In this study we tried to identify the genes that are up-regulated in NH. Design and Setting: The cDNA population prepared from DH was subtracted from that prepared from NH by a PCR-based cDNA subtraction method. The resultant cDNAs were cloned and sequenced. To confirm the up-regulation of the identified genes, a total of 35 parathyroid glands (18 DH, 16 NH, and one mixed) obtained from 21 patients were analyzed. Results: One of the nuclear genes identified was the PRKAR1A gene, which encodes type Iα regulatory subunit (RIα) of cAMP-dependent protein kinase (PKA). Immunohistochemical analysis demonstrated that RIα was abundantly expressed in the nodular region, whereas the adjacent diffuse region displayed relatively low expression. Northern and Western blot analyses demonstrated up-regulation of RIα expression in most NH tested. Determination of PKA activities revealed that free PKA activities measured in the absence of cAMP in the assay were inversely correlated with RIα expression, indicating the functional significance of RIα up-regulation. Conclusions: These results suggest that the aberrant expression of RIα is involved in the diffuse to nodular transformation of hyperplasia of parathyroid glands by impairing cAMP/PKA signal transduction.