LP533401 restores bone health in 5/6 nephrectomized rats by a decrease of gut-derived serotonin and regulation of serum phosphate through the inhibition of phosphate co-transporters expression in the kidneys
| Autor: | Krystyna Pawlak, Michał Doroszko, Urszula Łebkowska, Beata Znorko, Paweł Lipowicz, Bartlomiej Kalaska, Dariusz Pawlak, Radosław Zawadzki, Piotr Grabowski, Tomasz Domaniewski |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Serotonin Histology Physiology Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism Tryptophan Hydroxylase Kidney Calcitriol receptor Nephrectomy Phosphates Excretion 03 medical and health sciences 0302 clinical medicine Sodium-Phosphate Cotransporter Proteins Type II Bone Density Internal medicine medicine Animals Rats Wistar Renal Insufficiency Chronic Klotho Bone mineral Chemistry medicine.disease Uremia Rats Disease Models Animal 030104 developmental biology medicine.anatomical_structure Endocrinology Pyrimidines Cortical bone Kidney disease |
| Zdroj: | Bone. 113 |
| ISSN: | 1873-2763 |
| Popis: | LP533401 is an orally bioavailable small molecule that inhibits tryptophan hydroxylase-1, an enzyme responsible for the synthesis of gut-derived serotonin (GDS). Recently, we showed that increased GDS in rats with chronic kidney disease (CKD) affected bone strength and metabolism. We tested the hypothesis that treatment with LP533401 could reverse CKD-induced bone loss in uremia. Sixteen weeks after 5/6 nephrectomy, rats were randomized into untreated (CKD), treated with vehicle (VEH) and LP533401 at a dose of 30 or 100 mg/kg daily for 8 weeks. Treatment with LP533401 decreased serotonin turnover and restored bone mineral status, microarchitecture, and strength in CKD rats to the values observed in the controls. In parallel with the reduction of serotonin, serum phosphate levels also decreased, particularly in the LP533401, 100 mg/kg group. The mechanism underlying this phenomenon resulted from decreased expression of the renal VDR/FGF1R/Klotho/Npt2a/Npt2c axis, leading to elevated phosphate excretion in the kidneys. The elevated urinary phosphate excretion resulted in improved bone mineral status and strength in LP533401-treated rats. Unexpectedly, the standard VEH used in this model was able to reduce renal VDR/FGF1R/Klotho/Npt2a expression, leading to a compensatory increase in Npt2c mRNA levels, secondary disturbances in phosphate-regulated hormones and partial improvement in the mineral status of the trabecular bone. The decrease of serotonin synthesis together with the simultaneous reduction of renal Npt2a and Npt2c expression in rats treated with LP533401, 100 mg/kg led to an increase in 1,25(OH)2D3 levels; this mechanism seems to be particularly beneficial in relation to the mineral status of cortical bone. |
| Databáze: | OpenAIRE |
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