The use of LP533401 as a therapeutic option for renal osteodystrophy affects, renal calcium handling, vitamin D metabolism, and bone health in uremic rats

ABSTRACT

Background: Klotho is a key regulator of phosphate and Ca²⁺-transport in the kidney. Recently, we showed that treatment with LP533401 improved bone health in rats with chronic kidney disease (CKD) via the normalization of serum phosphate resulting from the reduced renal expression of phosphate cotransporters, including Klotho.

Methods: We evaluated the effect of LP533401 therapy on Klotho-expression-dependent Ca²⁺-transporters, renal calcium handling, and the potential consequences for the bone of uremic rats.

Results: Treatment with LP533401 and its vehicle resulted in the inhibition of transient receptor potential vanilloid receptor subtypes 5 and 6 (TRPV5, TRPV6) and calbindin (CaBP-28k, CaBP-9k) expression. The compensatory acceleration in renal expression of Na+/Ca²⁺-exchanger, 25-hydroxyvitamin d-1α-hydroxylase (CYP27B1), the intensification of vitamin D metabolism, and disruption of sophisticated balance between 1,25-dihydroxyvitamin D–serotonin was observed, especially in rats treated with LP533401. The imbalance between 1,25-dihydroxyvitamin D–serotonin levels led to intensified bone remodeling and improvement in bone geometry, mineral status, and strength in animals treated with LP533401.

Conclusion: The modulation of circulating serotonin and its relation to other regulators of calcium handling can play an important role in calcium homeostasis and bone integrity in CKD rats treated with LP533401.

KEYWORDS:

• Bone integrity
• chronic kidney disease
• gut-derived serotonin
• LP533401
• renal Ca²⁺-transporters
• urinary calcium excretion

Author contributions

All authors were involved in the conception, design, analysis and interpretation of the data. D Pawlak and K Pawlak drafted the paper and revised it critically for intellectual content. T Domaniewski and B Znorko gave the final approval of the final draft.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

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Additional information

Funding

This work was funded by grant number 2013/09/B/NZ7/00046 from National Science Centre (NCN), Poland and grants N/ST/ZB/18/001/2228 and N/ST/MN/17/001/2228 from the Medical University of Bialystok, Poland awarded to K Pawlak and B Znorko respectively. The study was conducted with the use of equipment purchased by the Medical University of Bialystok as part of the OP DEP 2007-2013, Priority Axis I.3, contract No. POPW.01.03.00-20-008/09.