The use of LP533401 as a therapeutic option for renal osteodystrophy affects, renal calcium handling, vitamin D metabolism, and bone health in uremic rats. (3rd April 2019)

• Record Type: Journal Article
• Authors: Pawlak, Dariusz; Domaniewski, Tomasz; Znorko, Beata; Pawlak, Krystyna
• Is Part Of: Expert opinion on therapeutic targets. Volume 23:Number 4(2019:Apr.)
• Page Start: 353
• Page End: 364
• Publication Date: 2019-04-03
• Subjects: Bone integrity -- chronic kidney disease -- gut-derived serotonin -- LP533401 -- renal Ca2+-transporters -- urinary calcium excretion; Drugs -- Research -- Periodicals; 615.072
• DOI: 10.1080/14728222.2019.1586883
• Languages: English
• ISSNs: 1744-7631

Abstract

ABSTRACT: Background : Klotho is a key regulator of phosphate and Ca 2+ -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 Ca 2+ -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+/Ca 2+ -exchanger, 25-hydroxyvitamind -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.