TY - JOUR
T1 - Hypomorphic expression of parathyroid Bmal1 disrupts the internal parathyroid circadian clock and increases parathyroid cell proliferation in response to uremia
AU - Egstrand, Søren
AU - Mace, Maria Lerche
AU - Morevati, Marya
AU - Nordholm, Anders
AU - Engelholm, Lars Henning
AU - Thomsen, Jesper Skovhus
AU - Brüel, Annemarie
AU - Naveh-Many, Tally
AU - Guo, Yuliu
AU - Olgaard, Klaus
AU - Lewin, Ewa
N1 - Funding Information:
Financial support was obtained from the Augustinus Foundation , the Eva and Henry Fraenkel Foundation, the Kirsten and Freddy Johansen Foundation, and the Helen and Ejnar Bjoernow Foundation. The VELUX Foundation is acknowledged for donating the μCT scanner.
Funding Information:
The authors thank Nina Vasiljevna Sejthen for her skilled technical support. Financial support was obtained from the Augustinus Foundation, the Eva and Henry Fraenkel Foundation, the Kirsten and Freddy Johansen Foundation, and the Helen and Ejnar Bjoernow Foundation. The VELUX Foundation is acknowledged for donating the μCT scanner.
Publisher Copyright:
© 2022 International Society of Nephrology
PY - 2022/6
Y1 - 2022/6
N2 - The molecular circadian clock is an evolutionary adaptation to anticipate recurring changes in the environment and to coordinate variations in activity, metabolism and hormone secretion. Parathyroid hyperplasia in uremia is a significant clinical challenge. Here, we examined changes in the transcriptome of the murine parathyroid gland over 24 hours and found a rhythmic expression of parathyroid signature genes, such as Casr, Vdr, Fgfr1 and Gcm2. Overall, 1455 genes corresponding to 6.9% of all expressed genes had significant circadian rhythmicity. Biological pathway analysis indicated that the circadian clock system is essential for the regulation of parathyroid cell function. To study this, a novel mouse strain with parathyroid gland-specific knockdown of the core clock gene Bmal1 (PTHcre;Bmal1flox/flox) was created. Dampening of the parathyroid circadian clock rhythmicity was found in these knockdown mice, resulting in abrogated rhythmicity of regulators of parathyroid cell proliferation such as Sp1, Mafb, Gcm2 and Gata3, indicating circadian clock regulation of these genes. Furthermore, the knockdown resulted in downregulation of genes involved in mitochondrial function and synthesis of ATP. When superimposed by uremia, these PTHcre;Bmal1flox/flox mice had an increased parathyroid cell proliferative response, compared to wild type mice. Thus, our findings indicate a role of the internal parathyroid circadian clock in the development of parathyroid gland hyperplasia in uremia.
AB - The molecular circadian clock is an evolutionary adaptation to anticipate recurring changes in the environment and to coordinate variations in activity, metabolism and hormone secretion. Parathyroid hyperplasia in uremia is a significant clinical challenge. Here, we examined changes in the transcriptome of the murine parathyroid gland over 24 hours and found a rhythmic expression of parathyroid signature genes, such as Casr, Vdr, Fgfr1 and Gcm2. Overall, 1455 genes corresponding to 6.9% of all expressed genes had significant circadian rhythmicity. Biological pathway analysis indicated that the circadian clock system is essential for the regulation of parathyroid cell function. To study this, a novel mouse strain with parathyroid gland-specific knockdown of the core clock gene Bmal1 (PTHcre;Bmal1flox/flox) was created. Dampening of the parathyroid circadian clock rhythmicity was found in these knockdown mice, resulting in abrogated rhythmicity of regulators of parathyroid cell proliferation such as Sp1, Mafb, Gcm2 and Gata3, indicating circadian clock regulation of these genes. Furthermore, the knockdown resulted in downregulation of genes involved in mitochondrial function and synthesis of ATP. When superimposed by uremia, these PTHcre;Bmal1flox/flox mice had an increased parathyroid cell proliferative response, compared to wild type mice. Thus, our findings indicate a role of the internal parathyroid circadian clock in the development of parathyroid gland hyperplasia in uremia.
KW - CKD
KW - Gata3
KW - Gcm2
KW - MafB
KW - RNAseq
KW - secondary hyperparathyroidism
U2 - 10.1016/j.kint.2022.02.018
DO - 10.1016/j.kint.2022.02.018
M3 - Journal article
C2 - 35276205
AN - SCOPUS:85128240422
VL - 101
SP - 1232
EP - 1250
JO - Kidney International. Supplement
JF - Kidney International. Supplement
SN - 0098-6577
IS - 6
ER -