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 -