Abstract
Activin A is a new fascinating player in chronic kidney disease-mineral and bone disorder (CKD-MBD), which is implicated in progressive renal disease, vascular calcification, and osteodystrophy. Plasma activin A rises early in the progression of renal disease. Disruption of circadian rhythms is related to increased risk of several diseases and circadian rhythms are observed in mineral homeostasis, bone parameters, and plasma levels of phosphate and PTH. Therefore, we examined the circadian rhythm of activin A and CKD-MBD-related parameters (phosphate, PTH, FGF23, and klotho) in healthy controls and CKD rats (5/6 nephrectomy) on high-, standard- and low-dietary phosphate contents as well as during fasting conditions. Plasma activin A exhibited circadian rhythmicity in healthy control rats with fourfold higher values at acrophase compared with nadir. The rhythm was obliterated in CKD. Activin A was higher in CKD rats compared with controls when measured at daytime but not significantly when measured at evening/nighttime, stressing the importance of time-specific reference intervals when interpreting plasma values. Plasma phosphate, PTH, and FGF23 all showed circadian rhythms in control rats, which were abolished or disrupted in CKD. Plasma klotho did not show circadian rhythm. Thus, the present investigation shows, for the first time, circadian rhythm of plasma activin A. The rhythmicity is severely disturbed by CKD and is associated with disturbed rhythms of phosphate and phosphate-regulating hormones PTH and FGF23, indicating that disturbed circadian rhythmicity is an important feature of CKD-MBD.
Highlights
Activin A is a member of the transforming growth factor beta (TGF-β) family of proteins produced by many cell types throughout development [7]
This circadian rhythmicity was obliterated in all chronic kidney disease (CKD) rats, even though some fluctuations of plasma activin A levels were seen in the PNX rats on different dietary P content (Fig. 1a, c–e)
In CKD rats, significant correlations appeared between activin A and P (p < 0.05, r2 = 0.07) and activin A and fibroblast growth factor 23 (FGF23) (p < 0.05, r2 = 0.05) but not between activin A and parathyroid hormone (PTH) (Fig. 2b, d, f)
Summary
Activin A is a member of the transforming growth factor beta (TGF-β) family of proteins produced by many cell types throughout development [7]. It participates in regulation of several biological processes, including cell differentiation, proliferation, and inflammatory response. Activin A mediates its biological effects through a complex of transmembrane receptor serine/threonine kinases. Activin A binds to activin A receptor type II (ActRllA), forms a complex with ALK4. Phosphorylation of ALK4 activates Smad2/3 and forms a complex together with Smad that translocate to the nucleus to regulate gene expression [7]. Preventing ActRllA signaling with a fusion protein, ACE-
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