The Pharmacological Effect and Mechanism of Lanthanum Hydroxide on Vascular Calcification Caused by Chronic Renal Failure Hyperphosphatemia

Abstract

ObjectiveThe present work aimed to explore the efficacy of lanthanum hydroxide in managing the vascular calcification induced by hyperphosphate in chronic renal failure (CRF) as well as the underlying mechanism.MethodsRats were randomly allocated to five groups: normal diet control, CKD hyperphosphatemia model, CKD model treated with lanthanum hydroxide, CKD model receiving lanthanum carbonate treatment, together with CKD model receiving calcium carbonate treatment. The serum biochemical and kidney histopathological parameters were analyzed. The aortic vessels were subjected to Von Kossa staining, CT scan and proteomic analysis. In vitro, the calcium content and ALP activity were measured, and RT-PCR (SM22α, Runx2, BMP-2, and TRAF6) and Western blot (SM22α, Runx2, BMP-2, TRAF6, and NF-κB) were performed.ResultsIn the lanthanum hydroxide group, serum biochemical and kidney histopathological parameters were significantly improved compared with the model group, indicating the efficacy of lanthanum hydroxide in postponing CRF progression and in protecting renal function. In addition, applying lanthanum hydroxide postponed hyperphosphatemia-mediated vascular calcification in CKD. Furthermore, lanthanum hydroxide was found to mitigate vascular calcification via the NF-κB signal transduction pathway. For the cultured VSMCs, lanthanum chloride (LaCl3) alleviated phosphate-mediated calcification and suppressed the activation of NF-κB as well as osteo-/chondrogenic signal transduction. Lanthanum hydroxide evidently downregulated NF-κB, BMP-2, Runx2, and TRAF6 expression.ConclusionLanthanum hydroxide protects against renal failure and reduces the phosphorus level in serum to postpone vascular calcification progression.

Lanthanum hydroxide protects kidney through gut microbiota in a rat model of chronic kidney disease

“…And lanthanum hydroxide delays the development of vascular calcification through inhibiting NF‐κB pathway activation via La 3+ . 27 In this study, we found that lanthanum hydroxide regulates the homeostasis of gut microbiota, affects amino acid metabolism, increases urinary ammonium circulation, and ultimately plays a role in kidney protection in CKD rat models.…”

Nitrogen-containing bisphosphonate induces enhancement of OPG expression and inhibition of RANKL expression via inhibition of farnesyl pyrophosphate synthase to inhibit the osteogenic differentiation and calcification in vascular smooth muscle cells

“…In adition, previous studies showed RANKL could promote the osteogenic differentiation and calci cation via the RANKL/RANK signaling pathway in VSMCs, which also could up-regulate the expression of Runx2 and OPN [24,25]. OPG can bind RANKL competitively to block the osteogenic differentiation and calci cation in VSMCs [24,25].…”

“…In terms of the osteogenic differentiation and calci cation in VSMCs(Figure 2), Runx2 is a key marker to drive this phenotypic differentiation, which is usually up-regulated during the osteogenic differentiation in VSMCs, promotes the expression of downstream osteogenic marker such as OPN, promotes the secretion of calci ed vesicles, and nally leads to the deposition of calcium-phosphate complexes in the vascular wall [26,27]. In adition, previous studies showed RANKL could promote the osteogenic differentiation and calci cation via the RANKL/RANK signaling pathway in VSMCs, which also could up-regulate the expression of Runx2 and OPN [24,25]. OPG can bind RANKL competitively to block the osteogenic differentiation and calci cation in VSMCs [24,25].…”

“…However, in different cells, different concentrations of N-BP regulate OPG and RANKL in different directions [19][20][21][22][23].Regarding the mechanism of VSMCs osteogenic differentiation and calci cation, RANKL can promote the the osteogenic differentiation and calci cation of VSMCs via the RANKL/RANK signaling pathway. OPG can bind RANKL competitively to block the RANKL/RANK signaling pathway,which play a protective role in the osteogenic differentiation and calci cation of VSMCs Figure 2 (24,25). If N-BP can increase OPG and inhibit RANKL in VSMCs, osteogenic differentiation and calci cation of VSMCs may be alleviated.…”

Metabolomics of clinical samples reveal the treatment mechanism of lanthanum hydroxide on vascular calcification in chronic kidney disease

“…Lanthanum phosphate has low water solubility, does not pass easily through the intestinal wall, and can be excreted through the feces, thereby achieving the effect of alleviating renal failure in CKD rat models, decreasing serum phosphorus levels, and inhibiting vascular calcification, equivalent to the effects of lanthanum carbonate (LC). 15 , 16 ) LC has been used clinically and is regarded as safe, 17 ) so it is suggested that the safety of LH may also be good. Because of the long-term administration in our experiment, there is a very small amount of absorption of lanthanum ions.…”