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


METHODS
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 Ialpha regulatory subunit (RIalpha) of cAMP-dependent protein kinase (PKA). Immunohistochemical analysis demonstrated that RIalpha 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 RIalpha 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 RIalpha expression, indicating the functional significance of RIalpha up-regulation.


CONCLUSIONS
These results suggest that the aberrant expression of RIalpha is involved in the diffuse to nodular transformation of hyperplasia of parathyroid glands by impairing cAMP/PKA signal transduction.
Hibi
Yatsuka
Y
Department of Endocrinology and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Kambe
Fukushi
F
Tominaga
Yoshihiro
Y
Mizuno
Yutaka
Y
Kobayashi
Hironobu
H
Iwase
Katsumi
K
Imai
Tsuneo
T
Seo
Hisao
H
D015152:Blotting, Northern; D015153:Blotting, Western; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000150:complications / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D009693:Nucleic Acid Hybridization; D010280:Parathyroid Glands / Q000201:enzymology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D015854:Up-Regulation
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D011506:Proteins; D012313:RNA; D017868:Cyclic AMP-Dependent Protein Kinases