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

Lulu Zhao,Bing Li,Yang Liu,Jian Hao,Jie Gao,Ruilan Han,Jianrong Zhao,Shengnan Wang,Yan Meng,Ren Bu,Hong Liu,Gang Li,Xiaoli Du

doi:10.3389/fcell.2021.639127

Lulu Zhao, Bing Li + Show 11 more

Open Access

https://doi.org/10.3389/fcell.2021.639127

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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.

Highlights

Chronic kidney disease (CKD) refers to any abnormality affecting the renal structure and function that lasts for over 3 months (Inker et al, 2014)
Lanthanum hydroxide protects against renal failure and reduces the phosphorus level in serum to postpone vascular calcification progression
In order to evaluate the protective effect of lanthanum hydroxide on the kidneys of CKD rats, we measured the levels of serum phosphorus, calcium, creatinine, and urea nitrogen at 4 and 8 weeks after treatment

Summary

Introduction

Chronic kidney disease (CKD) refers to any abnormality affecting the renal structure and function that lasts for over 3 months (Inker et al, 2014). Vascular calcification has been identified as the independent risk factor that increases CVD deaths among CKD cases. Many studies have confirmed that hyperphosphatemia can cause cardiovascular complications, such as vascular calcification and left ventricular hypertrophy, thereby increasing the risk of death from CVD in CKD patients (Goodman et al, 2000; Block et al, 2004; Russo et al, 2011; Briet and Burns, 2012; Smith, 2016). Intima and media calcification may be the main reason for the increased risk (10 to 100 fold) of cardiovascular death in patients with ESRD by 10 to 100 times (Huveneers et al, 2015). Studies have shown that calcification in the middle layer of arteries is a vital factor for predicting CVD-related mortality among ESRD cases (London et al, 2003)

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