Abstract
BackgroundChronic kidney disease (CKD) disrupts mineral homeostasis and its main underlying cause is secondary hyperparathyroidism (SHPT). We previously reported that calcium-sensing receptor (CaSR) mRNA and protein expression in parathyroid glands (PTGs) significantly decreased in a CKD rat model induced by a 5/6 nephrectomy that were fed a high phosphorus diet. However, there was a significant difference in the severity of CKD between high phosphorus and adequate phosphorus diet groups. Thus, it was unclear whether CKD environment or the high phosphorus diet influenced CaSR expression, and the underlying mechanism remains largely unknown.MethodsCKD was induced in rats with 0.75% adenine-containing diet. CKD and control rats were maintained for 5 days and 2 weeks on diets with 0.7% or 1.3% phosphorus. For gene expression analysis, quantitative real-time polymerase chain reaction was performed with TaqMan probes. Protein expression was analyzed by immunohistochemistry.ResultsPTG CaSR expression significantly decreased in the presence of a severe CKD environment, even without the high phosphate load. Ki67 expressing cells in PTGs were significantly higher only in the CKD rats fed a high phosphorus diet. Furthermore, among the many genes that could affect CaSR expression, only vitamin D receptor (VDR) and glial cells missing 2 (Gcm2) showed significant changes. Moreover, Gcm2 was significantly reduced at an early stage without significant changes in serum calcium, phosphorus and 1,25(OH)2 vitamin D, and there was no significant reduction in CaSR and VDR expressions. Then, significantly elevated Ki67-positive cell numbers were also only observed in the early CKD PTGs with high-phosphorus diets.ConclusionsOur data suggest that the cause of the decreased PTG CaSR expression is the reduction in VDR and Gcm2 expression; Gcm2 may play a role in the onset and progression of SHPT.
Highlights
Chronic kidney disease (CKD) disrupts mineral homeostasis and its main underlying cause is secondary hyperparathyroidism (SHPT)
In the Parathyroid gland (PTG), there is a gradual decrease in calcium-sensing receptor (CaSR) expression, which is important in the onset and progression of SHPT, with CKD progression [7], and it is associated with treatment resistance; the mechanism is largely unknown
We focused on the transcription factors that do not induce glial cells missing 2 (Gcm2) expression and cause aparathyroidism; it makes sense to focus on the genes such as paired box 1 (Pax1), paired box 9 (Pax9), sine oculis-related homeobox 1 (Six1), sine oculis-related homeobox 4 (Six4), eyes absent homolog 1 (Eya1), homeobox A3 (Hoxa3), forkhead box i1 (Foxi1), forkhead box i3 (Foxi3), trans-acting T-cell-specific transcription factor GATA-3 (GATA3), v-maf musculoaponeuroticfibrosarcoma oncogene homologue B (MafB), and t-box transcription factor 1 (Tbx1)
Summary
Chronic kidney disease (CKD) disrupts mineral homeostasis and its main underlying cause is secondary hyperparathyroidism (SHPT). We previously reported that calcium-sensing receptor (CaSR) mRNA and protein expression in parathyroid glands (PTGs) significantly decreased in a CKD rat model induced by a 5/6 nephrectomy that were fed a high phosphorus diet. There was a significant difference in the severity of CKD between high phosphorus and adequate phosphorus diet groups It was unclear whether CKD environment or the high phosphorus diet influenced CaSR expression, and the underlying mechanism remains largely unknown. CaSR mRNA and protein expressions significantly decreased in the rats fed a high phosphorus diet in our CKD rat model with SHPT induced by 5/6 nephrectomy [8]. Because in the nephrectomized rats, there was a significant difference in CKD severity between the high and adequate phosphorus diet groups, it was unclear which environment, the CKD environment or the high phosphorus diet, had a stronger influence on CaSR expression. The severity was expressed by the degree of the value
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